{"gene":"TAC1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2003,"finding":"TAC-1 (C. elegans TACC protein) physically interacts with ZYG-9 (XMAP215 family MAP) both in vitro and in vivo, and the two proteins mutually stabilize each other; TAC-1 centrosomal localization requires gamma-tubulin and Aurora-A kinase AIR-1 activity; loss of TAC-1 results in defective microtubule assembly as measured by FRAP.","method":"Co-immunoprecipitation (in vivo), in vitro binding assay, FRAP-based microtubule dynamics assay, RNAi knockdown, live imaging of GFP-TAC-1","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal in vitro and in vivo interaction, FRAP functional assay, replicated across three independent labs in the same year (PMIDs 12956950, 12956951, 12956952)","pmids":["12956950","12956951","12956952"],"is_preprint":false},{"year":2003,"finding":"TAC-1 depletion (RNAi) in C. elegans embryos produces very short centrosomal microtubules and short spindles without reducing alpha-tubulin intensity near centrosomes, indicating microtubule nucleation is intact but elongation/stabilization is impaired; TAC-1 and ZYG-9 are mutually dependent for centrosomal localization.","method":"RNAi, immunofluorescence, alpha-tubulin staining","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently in three labs, multiple orthogonal methods","pmids":["12956951","12956952"],"is_preprint":false},{"year":2007,"finding":"In C. elegans, TAC-1 physically interacts with ZYG-8 (doublecortin domain protein) through ZYG-8's doublecortin domain; TAC-1 and ZYG-8 form a complex that does not contain ZYG-9 in vivo; TAC-1 is required for correct ZYG-9 centrosomal enrichment; the ZYG-9-TAC-1 complex is required for correct anaphase spindle positioning.","method":"Co-immunoprecipitation, temperature-sensitive allele analysis, genetic epistasis, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis, multiple orthogonal methods in single rigorous study","pmids":["17666432"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, Shugoshin SGO-1 binds TAC-1 (TACC protein) and constrains TAC-1 to the ciliary basal body via the transition zone; TAC-1 activity must be maintained below a threshold at the ciliary base for correct cilia function, and SGO-1 participates in this regulation.","method":"Yeast two-hybrid / binding assay, genetic epistasis, immunofluorescence, cilia functional assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, genetic and localization evidence but limited biochemical reconstitution details in abstract","pmids":["37296204"],"is_preprint":false},{"year":2002,"finding":"Targeted deletion of the Tac1 gene (encoding substance P and neurokinin A) in mice diminishes anxiety- and depression-related behaviors, establishing that Tac1-encoded tachykinins are required for normal fear and stress responses.","method":"Tac1 knockout mice, behavioral paradigms (forced-swim, tail-suspension, open-field, elevated zero-maze, social interaction)","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined behavioral phenotypes across multiple paradigms, replicated across multiple behavioral tests","pmids":["12427862"],"is_preprint":false},{"year":2018,"finding":"Tac1-expressing glutamatergic neurons in the lateral/ventrolateral PAG facilitate the itch-scratching cycle via descending regulation; ablation or suppression of these neurons decreases itch-induced scratching; their activation-evoked scratching is suppressed by ablation of spinal GRPR neurons.","method":"Chemogenetics (DREADDs), optogenetics, neuron ablation, fiber photometry, behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal circuit-manipulation methods (chemogenetics, ablation, optogenetics) with defined behavioral readouts in single rigorous study","pmids":["30554781"],"is_preprint":false},{"year":2014,"finding":"Tac2 gene (encoding NkB) expressed in centromedial amygdala (CeM) neurons is required for fear memory consolidation; NkB and its receptor Nk3R mediate this effect; increased Tac2 expression or lentiviral CeA overexpression enhances fear consolidation, blocked by Nk3R antagonist osanetant; silencing Tac2-expressing neurons via DREADDs impairs fear consolidation.","method":"Lentiviral overexpression, DREADD-based silencing, pharmacological Nk3R antagonism, fear conditioning behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (gain-of-function, loss-of-function, pharmacology) with defined behavioral readout in single rigorous study","pmids":["24976214"],"is_preprint":false},{"year":2016,"finding":"In vivo optogenetic stimulation of CeA Tac2-expressing neurons (ChR2 knockin mice) during fear acquisition enhanced fear memory consolidation and drove action potential firing in vitro; Tac2-CeA neurons co-express striatal-enriched protein tyrosine phosphatase (STEP), which may regulate Nk3R signaling.","method":"Optogenetics (ChR2 in Tac2-Cre mice), in vitro electrophysiology, immunofluorescence","journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — optogenetics with behavioral readout and electrophysiology, single lab","pmids":["27238620"],"is_preprint":false},{"year":2018,"finding":"Chronic social isolation stress (2 weeks) in mice induces brain-wide upregulation of Tac2/NkB; systemic Nk3R antagonist prevents virtually all behavioral effects of chronic social isolation; enhancing NkB expression and release in group-housed mice phenocopies social isolation stress; dissociable region-specific requirements for Tac2 peptide and Nk3R in different behavioral changes.","method":"Viral vector-mediated NkB overexpression, pharmacological Nk3R antagonism, brain-wide circuit manipulation (chemogenetics/DREADDs), behavioral assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal gain- and loss-of-function methods across brain regions with rigorous behavioral readouts in single high-impact study","pmids":["29775595"],"is_preprint":false},{"year":2021,"finding":"Sex differences exist in Tac2 pathway regulation of fear memory consolidation: CeA-Tac2 antagonism impairs fear memory in males but enhances it in females; CeA-testosterone mediates Tac2 effects in males, CeA-estradiol in females; Akt/GSK3β/β-Catenin signaling mediates the sex-differential Tac2 pathway regulation.","method":"Pharmacogenetic inhibition (DREADDs), intracranial hormone manipulation, western blotting of signaling proteins, fear conditioning","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemogenetics, pharmacology, and signaling pathway analysis in single lab with multiple methods","pmids":["33941789"],"is_preprint":false},{"year":2020,"finding":"Tac1-expressing neurons in the nucleus accumbens (NAc) lateral shell project to ventral pallidum and contribute to stress-induced anhedonia-like behavior; selective inhibition and activation of Tac1-NAc neurons bidirectionally modulate stress susceptibility; inhibition of neurokinin 1 receptor promotes susceptibility to social stress.","method":"Chemogenetics (DREADDs), optogenetics, circuit tracing, behavioral assays (sucrose preference, social defeat)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional chemogenetic manipulation with circuit tracing, single lab","pmids":["33147466"],"is_preprint":false},{"year":2023,"finding":"Tac1 neurons in the NAc medial shell project to the lateral hypothalamic area (LH); the NAc-Tac1→LH pathway contributes to avoidance responses to aversive stimuli; medial prefrontal cortex sends excitatory inputs to NAc-Tac1 neurons regulating avoidance.","method":"Chemogenetics, optogenetic circuit dissection, anterograde/retrograde tracing, behavioral assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — optogenetic pathway dissection and chemogenetics in single lab","pmids":["36901777"],"is_preprint":false},{"year":2009,"finding":"REST (RE-1 silencing transcription factor) binds the 5' UTR of the TAC1 promoter and suppresses TAC1 expression; REST expression in breast cancer cells is inversely proportional to aggressiveness; REST knockdown increases TAC1 expression, proliferation, and migration in low-metastatic cells; ectopic REST in aggressive cells reduces these parameters.","method":"Reporter gene assays, western blot, RT-PCR, REST knockdown/overexpression, cell migration assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter binding combined with loss/gain-of-function in single lab with multiple readouts","pmids":["19246391"],"is_preprint":false},{"year":2007,"finding":"REST and NFκB synergistically repress TAC1 transcription in human mesenchymal stem cells; two REST-binding sites are adjacent to one NFκB site within exon 1 of the TAC1 promoter; ChIP and mutagenesis confirmed both factors cooperate for repression in neurogenic and cytokine-stimulated conditions.","method":"Chromatin immunoprecipitation (ChIP), reporter gene mutagenesis, loss-of-function (siRNA/dominant negative), transcription factor mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and mutagenesis in single lab with multiple functional assays","pmids":["17709376"],"is_preprint":false},{"year":2010,"finding":"TAC1 promoter requires synergy with a remote enhancer element (ECR2) to respond to MEK/ERK (MAPK) signaling in sensory neurons; antagonism of the MEK pathway blocks noxious stimulation-driven TAC1 enhancer-promoter synergy; capsaicin induction involves a non-cell-autonomous mechanism in larger diameter neurons.","method":"Comparative genomics (ECR identification), transgenic mouse reporter assays, pharmacological MEK inhibition, primary sensory neuron culture, capsaicin stimulation","journal":"Neuro-Signals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic reporters combined with pharmacological inhibition in primary cells, single lab","pmids":["21160161"],"is_preprint":false},{"year":2011,"finding":"NK1 receptor is expressed in all SP-expressing sensory neurons after capsaicin induction; an NK1 agonist activates both SP expression and the TAC1 ECR1 enhancer-promoter in larger diameter neurons, demonstrating an autocrine loop controlling TAC1 promoter activity in sensory neurons.","method":"Reporter gene assays, immunofluorescence, pharmacological NK1 agonist treatment, primary sensory neuron culture","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay plus pharmacological validation in primary neurons, single lab","pmids":["21294877"],"is_preprint":false},{"year":2011,"finding":"During MSC-to-neuron differentiation, CRE1 and CRE2/AP-1 sites in the TAC1 promoter are activated sequentially (days 6 and 12); decrease of REST activates JNK, which activates ATF-2 and AP-1 to bind CRE1 and CRE2/AP-1 respectively; JNK inhibition blocks TAC1 induction; transplanted JNK-pathway-active MSCs improve spinal cord injury in zebrafish.","method":"Reporter gene assays with CRE mutants, PKA/JNK inhibitors, ChIP, ectopic REST expression, in vivo zebrafish SCI model","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, mutagenesis, pharmacological inhibition) in single lab","pmids":["21671725"],"is_preprint":false},{"year":2007,"finding":"SDF-1α regulates TAC1 expression in bone marrow stromal cells via NF-κB; at high SDF-1α levels (≥50 ng/mL) NF-κB activation mediates repression of TAC1 within exon 1; substance P produced downstream does not regulate SDF-1α production (negative finding); substance P signals through NK1 (not NK2) receptor to stimulate hematopoiesis.","method":"Reporter gene assays, gel shift (EMSA), NF-κB mutant IκB transfection, Northern blot, ELISA, long-term culture-initiating cell assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, dominant-negative functional assay, and multiple readouts in single lab","pmids":["17277111"],"is_preprint":false},{"year":2008,"finding":"In non-tumorigenic breast cells, SDF-1α at low concentrations activates TAC1 via CRE sites through a non-canonical Gαi2-PI3K-PKCζ-p38-ERK pathway to phosphorylate CREB, distinct from the cAMP-PKA pathway used in bone marrow stromal cells.","method":"Reporter gene assays with CRE mutants, ICER co-transfection, western blot with pathway inhibitors, signaling inhibitor panel","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors with reporter assays, single lab","pmids":["18316470"],"is_preprint":false},{"year":2013,"finding":"MeCP2 binds directly to the TAC1 promoter in HEK cells as shown by ChIP; antiepileptic drug (valproic acid) treatment alters MeCP2 binding to TAC1 promoter; TAC1 promoter CpG hypermethylation correlates with reduced TAC1 expression in autism and seizure disorder.","method":"Chromatin immunoprecipitation (ChIP), DNA methylation profiling, Sequenom EpiTYPER validation, qRT-PCR","journal":"Journal of neurodevelopmental disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP in a single cell-line model with corroborating methylation profiling, single lab","pmids":["23759142"],"is_preprint":false},{"year":2007,"finding":"Post-transcriptional regulation of Tac1 mRNA in bone marrow stroma involves RNA-binding proteins (with differential binding kinetics for stimulatory vs. inhibitory cytokines) and cytokine-induced miRNAs that interact with the 3' UTR of Tac1 mRNA.","method":"RNA electrophoretic mobility shift assay (RNA-EMSA), miRNA detection/interaction assays","journal":"Brain, behavior, and immunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RNA-EMSA and miRNA detection, no identity of specific binding proteins/miRNAs, single lab","pmids":["18061399"],"is_preprint":false},{"year":2010,"finding":"Tac1-encoded tachykinins (substance P and neurokinin A) are required for morphine-induced respiratory depression and the aversive aspect of opioid withdrawal; in Tac1-/- mice morphine analgesia is enhanced and behavioral sensitization (addiction mechanism) is reduced.","method":"Tac1 knockout mice, morphine analgesic assays, naloxone-precipitated withdrawal, behavioral sensitization, conditioned place preference","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple behavioral readouts across analgesic, respiratory, and addiction paradigms, single lab","pmids":["20590634"],"is_preprint":false},{"year":2017,"finding":"Tac1 knockout male mice show delayed puberty, decreased Pdyn and Nos1 expression, and elevated GnRH levels; kisspeptin receptor (Kiss1R) and substance P receptor (NK1R) heterodimerize, suggesting SP tone alters GnRH neuron responsiveness to kisspeptin; Tac1-/- mice show decreased LH response to central kisspeptin and senktide administration despite intact GnRH neuron stimulation.","method":"Tac1 knockout mice, RT-qPCR, receptor heterodimerization assay (co-IP/FRET), electrophysiology of arcuate Kiss1 neurons, LH ELISA","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor heterodimerization assay plus KO phenotype and electrophysiology, single lab","pmids":["28444173"],"is_preprint":false},{"year":2017,"finding":"TAC1-encoded substance P and neurokinin A maintain basal cutaneous microcirculation; Tac1-/- mice show significantly lower basal postoperative skin microcirculation but mustard oil-induced neurogenic vasodilation is unaffected, while motor coordination is impaired in Tac1-/- mice.","method":"Tac1 knockout mice, laser Doppler imaging, Rota-Rod test, dynamic plantar aesthesiometry","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined physiological readouts, multiple functional measurements, single lab","pmids":["23499760"],"is_preprint":false},{"year":2019,"finding":"Tac1 knockout nociceptors display disrupted encoding of tonic suprathreshold mechanical stimuli and fail to develop mechanical sensitization after injury; Tac1-/- mice show reduced paw edema, hypersensitivity, and weight-bearing deficits after incision, and their nociceptors lack post-incision electrical hyperexcitability, despite normal CGRP upregulation.","method":"Tac1 knockout mice, in vivo electrophysiology of primary afferents, behavioral nociception assays, immunofluorescence","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo afferent electrophysiology combined with behavioral and immunohistochemical validation in KO model","pmids":["31012376"],"is_preprint":false},{"year":2015,"finding":"Absence of Tac1-encoded tachykinins (Tac1-/- mice) is associated with significantly lower spinal cord concentrations of opioid peptides endomorphin-2, leucine-enkephalin, and dynorphin A (Dyn A ~3-fold lower), suggesting tachykinin system supports endogenous opioid tone.","method":"HPLC-linear ion trap mass spectrometry (LC-MS/MRM) quantification of spinal cord neuropeptides in Tac1-/- vs wild-type mice","journal":"Neuropeptides","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous mass spectrometric quantification but single lab, single method","pmids":["26072188"],"is_preprint":false},{"year":2017,"finding":"Tac1 ablation in mice produces a lean phenotype with reduced food intake, altered circadian feeding rhythm (disrupted clock gene Cry1/2, Per1/2 expression in SCN, MBH, and liver), increased proopiomelanocortin (POMC) expression in MBH, resistance to diet-induced obesity, and improved glucose tolerance; Tac1 controls energy balance through the melanocortin system.","method":"Tac1 knockout mice, metabolic cage analysis, RT-qPCR, high-fat diet challenge, glucose/insulin tolerance tests, brown adipose tissue thermogenic assay","journal":"International journal of obesity (2005)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple metabolic and molecular readouts, single lab","pmids":["28775376"],"is_preprint":false},{"year":2017,"finding":"In Candida albicans, hyperactivated Tac1 (by gain-of-function mutations or xenobiotics) facilitates recruitment of the Mediator coactivator complex to the CDR1 promoter; CDR1 activation and azole resistance depend on the Tac1 C-terminal transcriptional activation domain (TAD) and Mediator tail module subunits; Tac1 hyperactivation correlates with Mediator-dependent Tac1 phosphorylation; the Tac1 middle region negatively regulates the TAD.","method":"Promoter ChIP of Mediator subunits, transcriptional activation domain mapping, Mediator tail subunit deletion strains, azole susceptibility testing","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP of coactivator recruitment combined with domain-deletion functional analysis, single lab","pmids":["28807920"],"is_preprint":false},{"year":2023,"finding":"In C. albicans Tac1, the N-terminal DNA binding domain (DBD) interacts with the Drug Responsive Element (DRE) in CDR1/CDR2 promoters; the C-terminal Acidic Activation Domain (AAD) interacts with TATA box binding protein (TBP); the Middle Homology Region (MHR) acts as a xenobiotic binding domain (XBD) important for drug resistance.","method":"Domain deletion/truncation analysis, reporter gene assays, protein-protein interaction assays (TBP binding), DRE binding assays","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain dissection with functional assays for DNA and protein binding, single lab","pmids":["37502396"],"is_preprint":false},{"year":2018,"finding":"C. albicans Tac1 and Znc1 are functionally activated by farnesol (quorum-sensing molecule) and together bind the CDR1 promoter to upregulate CDR1; CDR1 expression then facilitates farnesol efflux; Tac1 and Znc1 have overlapping but non-identical regulons.","method":"Tac1/Znc1 deletion strains, promoter-ChIP, CDR1 reporter assays, farnesol growth/efflux assays, RNA-seq","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, KO strains, and functional efflux assays with RNA-seq, single lab","pmids":["30104273"],"is_preprint":false},{"year":2023,"finding":"In Candida parapsilosis, gain-of-function mutation CpTac1-G650E causes 8-fold increase in fluconazole MIC and overexpression of CpCDR1, CpCDR1B, and CpCDR1C; correction of this mutation reduces MIC 16-fold; disruption of CDR1/CDR1B/CDR1C together reduces MIC 4-fold, establishing CpTac1 as a direct regulator of efflux pump-mediated triazole resistance.","method":"CRISPR-Cas9 precise editing (introduction and correction of CpTAC1 mutation), RNA-seq, RT-qPCR, broth microdilution susceptibility testing","journal":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","confidence":"High","confidence_rationale":"Tier 1 / Moderate — precise genome editing (introduction and reversion), RNA-seq, and susceptibility testing in single rigorous study","pmids":["37666448"],"is_preprint":false},{"year":2010,"finding":"TAC1 is expressed in the sheep pars tuberalis (PT) and strongly activated by long photoperiod; TAC1-encoded peptides (substance P and neurokinin A) act as prolactin secretagogues on primary pituitary cells, making TAC1 a candidate for the PT-expressed 'tuberalin' seasonal hormone regulator.","method":"Microarray, in situ hybridization, primary pituitary cell prolactin secretion assay","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional prolactin secretion assay on primary cells combined with expression mapping, single lab","pmids":["20434341"],"is_preprint":false},{"year":2025,"finding":"In indica rice, fine-tuning TAC1 expression levels via CRISPR-Cas9 editing of upstream and downstream non-coding regions produces gradient tiller angle changes proportional to TAC1 expression levels, with no effect on other agronomic traits; TAC1 is conserved across species including fruit trees.","method":"Multiplex CRISPR-Cas9 editing, RT-qPCR expression quantification, phenotypic analysis of homozygous allelic lines","journal":"Journal of integrative plant biology","confidence":"Low","confidence_rationale":"Tier 2 / Weak — plant ortholog (rice TAC1) not the human/mammalian TAC1 gene; included for completeness but represents a symbol collision with a plant gene","pmids":["40052456"],"is_preprint":false},{"year":2024,"finding":"In the spinal cord dorsal horn, Tac2-expressing neurons receive direct inhibitory input from Npy neurons; during chronic itch, Y1R expression on Tac2 neurons is reduced and NPY-Y1R inhibitory regulation of Tac2 neurons is diminished, contributing to mechanical hyperknesis.","method":"Rabies virus circuit tracing, chemogenetics, immunofluorescence, electrophysiology, transgenic mice","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — circuit tracing combined with chemogenetic manipulation and electrophysiology, single lab","pmids":["38164144"],"is_preprint":false},{"year":2025,"finding":"PBNTac1 neurons form close synaptic connections with CeATac1 neurons; activation of the PBNTac1→CeA pathway increases scratching in histamine-induced itch but not chloroquine-induced itch; inhibition of this pathway decreases histamine-induced scratching, defining a modality-specific itch circuit.","method":"Fiber photometry, chemogenetics (DREADDs), immunohistochemistry, behavioral itch assays","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple circuit methods with behavioral readouts, single lab","pmids":["39914640"],"is_preprint":false}],"current_model":"Human/mammalian TAC1 encodes the tachykinin neuropeptides substance P and neurokinin A, which act through NK1R (and NK2R) to modulate diverse processes including nociception, fear memory consolidation (via NkB/Tac2-related circuits in the amygdala), itch-scratching cycles (via Tac1+ PAG and amygdala neurons projecting to spinal GRPR neurons), stress-induced anhedonia (via NAc→ventral pallidum Tac1 circuits), circadian feeding and energy balance (through the melanocortin/POMC system), and reproductive function (by modulating GnRH neuron responsiveness through NK1R-Kiss1R heterodimerization); TAC1 transcription is repressed by REST and NFκB cooperatively, activated downstream of SDF-1α through CRE sites via JNK/ATF-2/AP-1 and a non-canonical Gαi2-PI3K-PKCζ-ERK pathway, and is regulated by MeCP2 binding and promoter methylation; in the fungal pathogen Candida albicans, the unrelated TAC1 gene encodes a zinc-cluster transcription factor whose gain-of-function mutations hyperactivate CDR1/CDR2 efflux pump expression via Mediator complex recruitment, conferring azole resistance."},"narrative":{"mechanistic_narrative":"The TAC1 symbol in this corpus resolves to at least three biologically unrelated genes, and the mammalian TAC1 entries describe a tachykinin neuropeptide precursor. In mammals, TAC1 encodes substance P and neurokinin A, neuropeptides whose loss diminishes anxiety- and depression-related behavior and disrupts stress and fear responses [PMID:12427862]. These peptides act largely through NK1R: Tac1-expressing neurons drive defined circuits including a lateral/ventrolateral PAG pathway that facilitates the itch-scratching cycle via spinal GRPR neurons [PMID:30554781], a nucleus accumbens shell projection to ventral pallidum that bidirectionally controls stress-induced anhedonia [PMID:33147466], and an accumbens medial-shell projection to lateral hypothalamus governing aversive avoidance [PMID:36901777]. TAC1 tachykinins are required for injury-induced nociceptor mechanical sensitization and hyperexcitability [PMID:31012376], for morphine-induced respiratory depression and opioid withdrawal aversion [PMID:20590634], and they support endogenous spinal opioid peptide tone [PMID:26072188]. Beyond the nervous system, TAC1 peptides maintain basal cutaneous microcirculation [PMID:23499760], modulate puberty and GnRH-neuron responsiveness to kisspeptin via NK1R-Kiss1R heterodimerization [PMID:28444173], control energy balance and circadian feeding through the melanocortin/POMC system [PMID:28775376], and act as prolactin secretagogues in the seasonally regulated pars tuberalis [PMID:20434341]. TAC1 transcription is repressed by REST, which cooperates synergistically with NFκB at sites within exon 1 [PMID:19246391, PMID:17709376], and is activated downstream of SDF-1α through CRE/CREB signaling using distinct pathways in different cell types—cAMP-independent Gαi2-PI3K-PKCζ-ERK signaling in breast cells [PMID:18316470]—together with JNK/ATF-2/AP-1 input and enhancer (ECR) synergy in differentiating and sensory neurons [PMID:21160161, PMID:21671725], plus MeCP2 binding and promoter CpG methylation [PMID:23759142]. Separately and unrelated to the neuropeptide gene, the C. elegans TAC-1 (a TACC-family microtubule-associated protein) and the Candida/Candida parapsilosis Tac1 (a zinc-cluster transcription factor) and a plant TAC1 (tiller angle control) appear in this corpus as symbol collisions describing entirely distinct proteins.","teleology":[{"year":2002,"claim":"Establishing whether TAC1-encoded tachykinins are dispensable for affective behavior, genetic ablation defined a required role in normal fear and stress responses.","evidence":"Tac1 knockout mice across multiple anxiety/depression behavioral paradigms","pmids":["12427862"],"confidence":"High","gaps":["Does not resolve which peptide (SP vs NkA) or which receptor mediates each behavior","Circuit/region of action not localized"]},{"year":2010,"claim":"To define the receptor-level and pathway logic of TAC1 transcription, studies showed REST and SDF-1α inputs converge on the promoter and that tachykinins regulate opioid-related physiology.","evidence":"Reporter assays, EMSA, ChIP, Tac1-KO opioid/withdrawal behavioral assays in stromal/sensory cells and mice","pmids":["19246391","17709376","17277111","18316470","20590634"],"confidence":"Medium","gaps":["Cell-type specificity of the non-canonical Gαi2-PI3K-PKCζ-ERK pathway not generalized","Endogenous miRNA/RNA-binding regulators of Tac1 mRNA not identified at molecular identity level"]},{"year":2011,"claim":"To explain stimulus-driven TAC1 induction in sensory neurons, work showed promoter activity requires remote enhancer (ECR) synergy with MEK/ERK and an autocrine NK1 feedback loop.","evidence":"Transgenic reporter assays, MEK/JNK inhibitors, NK1 agonist treatment, primary sensory neuron culture","pmids":["21160161","21294877","21671725"],"confidence":"Medium","gaps":["Non-cell-autonomous induction mechanism in large-diameter neurons not fully defined","In vivo relevance of the autocrine loop to nociception untested"]},{"year":2017,"claim":"Defining systemic and developmental roles, Tac1 ablation revealed contributions to puberty/GnRH responsiveness via NK1R-Kiss1R heterodimerization, energy balance through the melanocortin system, and cutaneous microcirculation.","evidence":"Tac1-KO mice with receptor heterodimerization assays, metabolic cage/glucose tests, laser Doppler imaging, prolactin secretion assays","pmids":["28444173","28775376","23499760","20434341"],"confidence":"Medium","gaps":["Direct structural confirmation of NK1R-Kiss1R heterodimer signaling consequences limited","Circadian feeding effect mechanism (clock gene regulation) not causally dissected"]},{"year":2020,"claim":"To map where TAC1 neurons act, circuit-level dissection defined PAG, NAc-shell, and NAc-medial-shell Tac1 projections controlling itch, anhedonia, and avoidance, respectively.","evidence":"Chemogenetics, optogenetics, anterograde/retrograde tracing, behavioral assays in mice","pmids":["30554781","33147466","36901777"],"confidence":"Medium","gaps":["Whether TAC1 peptide release (vs fast neurotransmission) drives each circuit effect is unresolved","Receptor identity at each downstream node not uniformly defined"]},{"year":2019,"claim":"To test TAC1's role in peripheral pain encoding, knockout afferent recordings showed tachykinins are required for injury-induced mechanical sensitization and nociceptor hyperexcitability.","evidence":"In vivo primary afferent electrophysiology and behavioral nociception in Tac1-KO mice","pmids":["31012376"],"confidence":"Medium","gaps":["Molecular target downstream of SP/NkA in sensitized afferents not identified","Relationship to CGRP (unchanged) signaling not mechanistically resolved"]},{"year":null,"claim":"The receptor-coupled signaling cascades and cell-type-specific circuit logic linking TAC1 peptide release to each behavioral and physiological outcome remain incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking SP vs NkA, NK1R vs NK2R, to specific phenotypes","Corpus is contaminated by unrelated TAC-1/Tac1 genes (C. elegans TACC protein, fungal zinc-cluster transcription factor, plant tiller-angle gene) that do not inform mammalian TAC1 function"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[22,31]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[25,31]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,5,10,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[22,26]}],"complexes":[],"partners":["NK1R","KISS1R"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20366","full_name":"Protachykinin-1","aliases":["PPT"],"length_aa":129,"mass_kda":15.0,"function":"Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles Is a ligand for TACR1, and triggers G protein-coupled receptor signaling via activation of phosphatidylinositol hydrolysis by phospholipase C. Substance P binding to TACR1 also triggers signaling via activation of adenylate cyclase activity which results in increased intracellular levels of cyclic AMP (cAMP) (By similarity). Is also a TACR3 agonist with low receptor affinity (PubMed:37391393). Basic secretagogue neuropeptide released from the terminals of specific sensory nerves (PubMed:30686732). Acts as a ligand for MRGPRX2 receptor in mast cells, initiating a signaling that mediates neurogenic inflammation and pain (PubMed:30686732, PubMed:34789875). Neurogenic inflammation includes mast cell activation, recruitment of immune cells and release of inflammatory mediators, such as cytokines and chemokines (By similarity). The inflammatory response can then activate or sensitize nociceptors, promoting pain (By similarity) Is a ligand for TACR2, and triggers G protein-coupled receptor signaling via activation of G(q) and phosphatidylinositol hydrolysis by phospholipase C (PubMed:35882833). Binding to TACR2 also triggers signaling via activation of adenylate cyclase activity which results in increased intracellular levels of cyclic AMP (cAMP)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P20366/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TAC1","total_profiled":1310},"omim":[{"mim_id":"611599","title":"MICRO RNA 206; MIR206","url":"https://www.omim.org/entry/611599"},{"mim_id":"610175","title":"MICRO RNA 130A; MIR130A","url":"https://www.omim.org/entry/610175"},{"mim_id":"604255","title":"LADYBIRD HOMEOBOX 1; LBX1","url":"https://www.omim.org/entry/604255"},{"mim_id":"300005","title":"METHYL-CpG-BINDING PROTEIN 2; MECP2","url":"https://www.omim.org/entry/300005"},{"mim_id":"162332","title":"TACHYKININ RECEPTOR 3; TACR3","url":"https://www.omim.org/entry/162332"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":223.0}],"url":"https://www.proteinatlas.org/search/TAC1"},"hgnc":{"alias_symbol":["NPK"],"prev_symbol":["TAC2","NKNA"]},"alphafold":{"accession":"P20366","domains":[{"cath_id":"-","chopping":"2-57","consensus_level":"high","plddt":72.3271,"start":2,"end":57}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20366","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20366-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20366-F1-predicted_aligned_error_v6.png","plddt_mean":66.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAC1","jax_strain_url":"https://www.jax.org/strain/search?query=TAC1"},"sequence":{"accession":"P20366","fasta_url":"https://rest.uniprot.org/uniprotkb/P20366.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20366/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20366"}},"corpus_meta":[{"pmid":"18363649","id":"PMC_18363649","title":"An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1.","date":"2008","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18363649","citation_count":267,"is_preprint":false},{"pmid":"17908158","id":"PMC_17908158","title":"TAC1, a major quantitative trait locus controlling tiller angle in rice.","date":"2007","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17908158","citation_count":232,"is_preprint":false},{"pmid":"29775595","id":"PMC_29775595","title":"The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/29775595","citation_count":211,"is_preprint":false},{"pmid":"12956950","id":"PMC_12956950","title":"TAC-1 and ZYG-9 form a complex that promotes microtubule assembly in C. elegans embryos.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12956950","citation_count":126,"is_preprint":false},{"pmid":"12427862","id":"PMC_12427862","title":"Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12427862","citation_count":110,"is_preprint":false},{"pmid":"25046442","id":"PMC_25046442","title":"Impact of long-term N, P, K, and NPK fertilization on the composition and potential functions of the bacterial community in grassland soil.","date":"2014","source":"FEMS microbiology ecology","url":"https://pubmed.ncbi.nlm.nih.gov/25046442","citation_count":110,"is_preprint":false},{"pmid":"30554781","id":"PMC_30554781","title":"Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/30554781","citation_count":109,"is_preprint":false},{"pmid":"28905629","id":"PMC_28905629","title":"Nanoparticle and Ionic Zn Promote Nutrient Loading of Sorghum Grain under Low NPK Fertilization.","date":"2017","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28905629","citation_count":100,"is_preprint":false},{"pmid":"12956951","id":"PMC_12956951","title":"TAC-1, a regulator of microtubule length in the C. elegans embryo.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12956951","citation_count":96,"is_preprint":false},{"pmid":"27814357","id":"PMC_27814357","title":"A Novel Tiller Angle Gene, TAC3, together with TAC1 and D2 Largely Determine the Natural Variation of Tiller Angle in Rice Cultivars.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27814357","citation_count":95,"is_preprint":false},{"pmid":"12956952","id":"PMC_12956952","title":"Caenorhabditis elegans TAC-1 and ZYG-9 form a complex that is essential for long astral and spindle microtubules.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12956952","citation_count":88,"is_preprint":false},{"pmid":"24976214","id":"PMC_24976214","title":"A role for Tac2, NkB, and Nk3 receptor in normal and dysregulated fear memory consolidation.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/24976214","citation_count":84,"is_preprint":false},{"pmid":"24486589","id":"PMC_24486589","title":"Functional identification of cancer-specific methylation of CDO1, HOXA9, and TAC1 for the diagnosis of lung cancer.","date":"2014","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/24486589","citation_count":70,"is_preprint":false},{"pmid":"24243794","id":"PMC_24243794","title":"Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence.","date":"2013","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/24243794","citation_count":70,"is_preprint":false},{"pmid":"32060036","id":"PMC_32060036","title":"Mapping of Sensory Nerve Subsets within the Vagal Ganglia and the Brainstem Using Reporter Mice for Pirt, TRPV1, 5-HT3, and Tac1 Expression.","date":"2020","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/32060036","citation_count":69,"is_preprint":false},{"pmid":"20434341","id":"PMC_20434341","title":"Identification of Eya3 and TAC1 as long-day signals in the sheep pituitary.","date":"2010","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/20434341","citation_count":69,"is_preprint":false},{"pmid":"22893725","id":"PMC_22893725","title":"Increased neurokinin B (Tac2) expression in the mouse arcuate nucleus is an early marker of pubertal onset with differential sensitivity to sex steroid-negative feedback than Kiss1.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22893725","citation_count":68,"is_preprint":false},{"pmid":"34311410","id":"PMC_34311410","title":"Heterotrophic nitrification and aerobic denitrification by a novel Acinetobacter sp. TAC-1 at low temperature and high ammonia nitrogen.","date":"2021","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/34311410","citation_count":67,"is_preprint":false},{"pmid":"19246391","id":"PMC_19246391","title":"RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19246391","citation_count":62,"is_preprint":false},{"pmid":"32999383","id":"PMC_32999383","title":"Different organic manure sources and NPK fertilizer on soil chemical properties, growth, yield and quality of okra.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32999383","citation_count":54,"is_preprint":false},{"pmid":"21980509","id":"PMC_21980509","title":"The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21980509","citation_count":51,"is_preprint":false},{"pmid":"28807920","id":"PMC_28807920","title":"Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans.","date":"2017","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/28807920","citation_count":47,"is_preprint":false},{"pmid":"31812023","id":"PMC_31812023","title":"Optimization of NPK fertilization combined with phytoremediation of cadmium contaminated soil by orthogonal experiment.","date":"2019","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/31812023","citation_count":44,"is_preprint":false},{"pmid":"24051054","id":"PMC_24051054","title":"Deciphering azole resistance mechanisms with a focus on transcription factor-encoding genes TAC1, MRR1 and UPC2 in a set of fluconazole-resistant clinical isolates of Candida albicans.","date":"2013","source":"International journal of antimicrobial agents","url":"https://pubmed.ncbi.nlm.nih.gov/24051054","citation_count":41,"is_preprint":false},{"pmid":"33941789","id":"PMC_33941789","title":"Sex differences in fear memory consolidation via Tac2 signaling in mice.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33941789","citation_count":37,"is_preprint":false},{"pmid":"27238620","id":"PMC_27238620","title":"Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning.","date":"2016","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27238620","citation_count":36,"is_preprint":false},{"pmid":"22272772","id":"PMC_22272772","title":"Genetic marking and characterization of Tac2-expressing neurons in the central and peripheral nervous system.","date":"2012","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/22272772","citation_count":35,"is_preprint":false},{"pmid":"26862996","id":"PMC_26862996","title":"ERα in Tac2 Neurons Regulates Puberty Onset in Female Mice.","date":"2016","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26862996","citation_count":35,"is_preprint":false},{"pmid":"29736251","id":"PMC_29736251","title":"Alteration of TAC1 expression in Prunus species leads to pleiotropic shoot phenotypes.","date":"2018","source":"Horticulture research","url":"https://pubmed.ncbi.nlm.nih.gov/29736251","citation_count":35,"is_preprint":false},{"pmid":"17709376","id":"PMC_17709376","title":"Synergy between the RE-1 silencer of transcription and NFkappaB in the repression of the neurotransmitter gene TAC1 in human mesenchymal stem cells.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17709376","citation_count":34,"is_preprint":false},{"pmid":"19070410","id":"PMC_19070410","title":"Evaluation of physiological, growth and yield responses of a tropical oil crop (Brassica campestris L. var. Kranti) under ambient ozone pollution at varying NPK levels.","date":"2008","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/19070410","citation_count":34,"is_preprint":false},{"pmid":"17666432","id":"PMC_17666432","title":"ZYG-9, TAC-1 and ZYG-8 together ensure correct microtubule function throughout the cell cycle of C. elegans embryos.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17666432","citation_count":30,"is_preprint":false},{"pmid":"28444173","id":"PMC_28444173","title":"Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse.","date":"2017","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28444173","citation_count":29,"is_preprint":false},{"pmid":"23499760","id":"PMC_23499760","title":"Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions.","date":"2013","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/23499760","citation_count":28,"is_preprint":false},{"pmid":"33147466","id":"PMC_33147466","title":"Nucleus Accumbens Tac1-Expressing Neurons Mediate Stress-Induced Anhedonia-like Behavior in Mice.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33147466","citation_count":25,"is_preprint":false},{"pmid":"21294877","id":"PMC_21294877","title":"Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones.","date":"2011","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/21294877","citation_count":24,"is_preprint":false},{"pmid":"29576999","id":"PMC_29576999","title":"The effect of chitosan-PMAA-NPK nanofertilizer on Pisum sativum plants.","date":"2018","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/29576999","citation_count":23,"is_preprint":false},{"pmid":"30104273","id":"PMC_30104273","title":"Candida albicans Zn Cluster Transcription Factors Tac1 and Znc1 Are Activated by Farnesol To Upregulate a Transcriptional Program Including the Multidrug Efflux Pump CDR1.","date":"2018","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/30104273","citation_count":22,"is_preprint":false},{"pmid":"17277111","id":"PMC_17277111","title":"Stromal derived growth factor-1alpha: another mediator in neural-emerging immune system through Tac1 expression in bone marrow stromal cells.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17277111","citation_count":22,"is_preprint":false},{"pmid":"29478144","id":"PMC_29478144","title":"Integration of transcriptomic and cytoarchitectonic data implicates a role for MAOA and TAC1 in the limbic-cortical network.","date":"2018","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/29478144","citation_count":21,"is_preprint":false},{"pmid":"37666448","id":"PMC_37666448","title":"Mutations in TAC1 and ERG11 are major drivers of triazole antifungal resistance in clinical isolates of Candida parapsilosis.","date":"2023","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37666448","citation_count":21,"is_preprint":false},{"pmid":"24735328","id":"PMC_24735328","title":"Electrophysiology of arcuate neurokinin B neurons in female Tac2-EGFP transgenic mice.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24735328","citation_count":20,"is_preprint":false},{"pmid":"30485833","id":"PMC_30485833","title":"LOC134466 methylation promotes oncogenesis of endometrial carcinoma through LOC134466/hsa-miR-196a-5p/TAC1 axis.","date":"2018","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/30485833","citation_count":20,"is_preprint":false},{"pmid":"25659412","id":"PMC_25659412","title":"Chronic oestradiol reduces the dendritic spine density of KNDy (kisspeptin/neurokinin B/dynorphin) neurones in the arcuate nucleus of ovariectomised Tac2-enhanced green fluorescent protein transgenic mice.","date":"2015","source":"Journal of neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25659412","citation_count":20,"is_preprint":false},{"pmid":"21160161","id":"PMC_21160161","title":"Long-range regulatory synergy is required to allow control of the TAC1 locus by MEK/ERK signalling in sensory neurones.","date":"2010","source":"Neuro-Signals","url":"https://pubmed.ncbi.nlm.nih.gov/21160161","citation_count":20,"is_preprint":false},{"pmid":"38624217","id":"PMC_38624217","title":"Precise genome editing underlines the distinct contributions of mutations in ERG11, ERG3, MRR1, and TAC1 genes to antifungal resistance in Candida parapsilosis.","date":"2024","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/38624217","citation_count":20,"is_preprint":false},{"pmid":"31012376","id":"PMC_31012376","title":"Tachykinins modulate nociceptive responsiveness and sensitization: In vivo electrical characterization of primary sensory neurons in tachykinin knockout (Tac1 KO) mice.","date":"2019","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/31012376","citation_count":20,"is_preprint":false},{"pmid":"29682090","id":"PMC_29682090","title":"The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis.","date":"2018","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29682090","citation_count":19,"is_preprint":false},{"pmid":"31466523","id":"PMC_31466523","title":"Tac2-N acts as a novel oncogene and promotes tumor metastasis via activation of NF-κB signaling in lung cancer.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31466523","citation_count":17,"is_preprint":false},{"pmid":"36901777","id":"PMC_36901777","title":"A Nucleus Accumbens Tac1 Neural Circuit Regulates Avoidance Responses to Aversive Stimuli.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36901777","citation_count":15,"is_preprint":false},{"pmid":"37368599","id":"PMC_37368599","title":"Triazine Herbicide and NPK Fertilizer Exposure: Accumulation of Heavy Metals and Rare Earth Elements, Effects on Cuticle Melanization, and Immunocompetence in the Model Species Tenebrio molitor.","date":"2023","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/37368599","citation_count":14,"is_preprint":false},{"pmid":"17409218","id":"PMC_17409218","title":"Nuclear factor-kappaB accounts for the repressor effects of high stromal cell-derived factor-1alpha levels on Tac1 expression in nontumorigenic breast cells.","date":"2007","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/17409218","citation_count":14,"is_preprint":false},{"pmid":"21671725","id":"PMC_21671725","title":"Developmental regulation of TAC1 in peptidergic-induced human mesenchymal stem cells: implication for spinal cord injury in zebrafish.","date":"2011","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/21671725","citation_count":14,"is_preprint":false},{"pmid":"30682802","id":"PMC_30682802","title":"Co-Application of Milk Tea Waste and NPK Fertilizers to Improve Sandy Soil Biochemical Properties and Wheat Growth.","date":"2019","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30682802","citation_count":14,"is_preprint":false},{"pmid":"22868114","id":"PMC_22868114","title":"Nutritional and antioxidant profiles of pumpkin (Cucurbita pepo Linn.) immature and mature fruits as influenced by NPK fertilizer.","date":"2012","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22868114","citation_count":13,"is_preprint":false},{"pmid":"33461013","id":"PMC_33461013","title":"Transforming wet blue leather and potato peel into an eco-friendly bio-organic NPK fertilizer for intensifying crop productivity and retrieving value-added recyclable chromium salts.","date":"2021","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/33461013","citation_count":13,"is_preprint":false},{"pmid":"15620584","id":"PMC_15620584","title":"Amelioration of Indian urban air pollution phytotoxicity in Beta vulgaris L. by modifying NPK nutrients.","date":"2005","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/15620584","citation_count":13,"is_preprint":false},{"pmid":"35729637","id":"PMC_35729637","title":"Hyperandrogenism induces proportional changes in the expression of Kiss-1, Tac2, and DynA in hypothalamic KNDy neurons.","date":"2022","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/35729637","citation_count":12,"is_preprint":false},{"pmid":"35178132","id":"PMC_35178132","title":"The Neuropeptide-Related HERC5/TAC1 Interactions May Be Associated with the Dysregulation of lncRNA GAS5 Expression in Gestational Diabetes Mellitus Exosomes.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/35178132","citation_count":12,"is_preprint":false},{"pmid":"17376622","id":"PMC_17376622","title":"Tachykinin 1 (TAC1) gene SNPs and haplotypes with autism: a case-control study.","date":"2007","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/17376622","citation_count":11,"is_preprint":false},{"pmid":"15729363","id":"PMC_15729363","title":"Haplotype analysis of the preprotachykinin-1 (TAC1) gene in multiple sclerosis.","date":"2005","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15729363","citation_count":11,"is_preprint":false},{"pmid":"23759142","id":"PMC_23759142","title":"Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene.","date":"2013","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/23759142","citation_count":11,"is_preprint":false},{"pmid":"20590634","id":"PMC_20590634","title":"Increased morphine analgesia and reduced side effects in mice lacking the tac1 gene.","date":"2010","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20590634","citation_count":11,"is_preprint":false},{"pmid":"15207300","id":"PMC_15207300","title":"Comparative effectiveness of cattle manure, poultry manure, phosphocompost and fertilizer-NPK on three cropping systems in vertisols of semi-arid tropics. II. Dry matter yield, nodulation, chlorophyll content and enzyme activity.","date":"2004","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/15207300","citation_count":11,"is_preprint":false},{"pmid":"33867115","id":"PMC_33867115","title":"A Second Wave for the Neurokinin Tac2 Pathway in Brain Research.","date":"2021","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33867115","citation_count":10,"is_preprint":false},{"pmid":"36169896","id":"PMC_36169896","title":"Expression pattern of drug-resistance genes ERG11 and TAC1 in Candida albicans Clinical isolates.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36169896","citation_count":9,"is_preprint":false},{"pmid":"18061399","id":"PMC_18061399","title":"Tac1 regulation by RNA-binding protein and miRNA in bone marrow stroma: Implication for hematopoietic activity.","date":"2007","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18061399","citation_count":9,"is_preprint":false},{"pmid":"31210930","id":"PMC_31210930","title":"Effects of NPK and biochar fertilized soil on the proximate composition and mineral evaluation of maize flour.","date":"2018","source":"Food science & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/31210930","citation_count":9,"is_preprint":false},{"pmid":"17175032","id":"PMC_17175032","title":"The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis.","date":"2006","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/17175032","citation_count":8,"is_preprint":false},{"pmid":"35371119","id":"PMC_35371119","title":"Influence of Nutrient (NPK) Factors on Growth, and Pharmacodynamic Component Biosynthesis of Atractylodes chinensis: An Insight on Acetyl-CoA Carboxylase (ACC), 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR), and Farnesyl Pyrophosphate Synthase (FPPS) Signaling Responses.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/35371119","citation_count":8,"is_preprint":false},{"pmid":"28775376","id":"PMC_28775376","title":"Altered circadian feeding behavior and improvement of metabolic syndrome in obese Tac1-deficient mice.","date":"2017","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/28775376","citation_count":8,"is_preprint":false},{"pmid":"18316470","id":"PMC_18316470","title":"Stromal-derived factor-1alpha induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells.","date":"2008","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18316470","citation_count":8,"is_preprint":false},{"pmid":"32194717","id":"PMC_32194717","title":"Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32194717","citation_count":8,"is_preprint":false},{"pmid":"20033737","id":"PMC_20033737","title":"Can NPK fertilizers enhance seedling growth and mycorrhizal status of Tuber melanosporum-inoculated Quercus ilex seedlings?","date":"2009","source":"Mycorrhiza","url":"https://pubmed.ncbi.nlm.nih.gov/20033737","citation_count":8,"is_preprint":false},{"pmid":"37765463","id":"PMC_37765463","title":"Beyond NPK: Mineral Nutrient-Mediated Modulation in Orchestrating Flowering Time.","date":"2023","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37765463","citation_count":7,"is_preprint":false},{"pmid":"32989391","id":"PMC_32989391","title":"Tac2-N serves an oncogenic role and promotes drug resistance in human gastric cancer cells.","date":"2020","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32989391","citation_count":7,"is_preprint":false},{"pmid":"29485996","id":"PMC_29485996","title":"Characterization of knockin mice at the Rosa26, Tac1 and Plekhg1 loci generated by homologous recombination in oocytes.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29485996","citation_count":7,"is_preprint":false},{"pmid":"36989993","id":"PMC_36989993","title":"Comparative transcriptome analyses under individual and combined nutrient starvations provide insights into N/P/K interactions in rice.","date":"2023","source":"Plant physiology and biochemistry : PPB","url":"https://pubmed.ncbi.nlm.nih.gov/36989993","citation_count":7,"is_preprint":false},{"pmid":"30769143","id":"PMC_30769143","title":"Exploring the involvement of Tac2 in the mouse hippocampal stress response through gene networking.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30769143","citation_count":6,"is_preprint":false},{"pmid":"17521418","id":"PMC_17521418","title":"Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.","date":"2007","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17521418","citation_count":6,"is_preprint":false},{"pmid":"23065762","id":"PMC_23065762","title":"Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids.","date":"2012","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/23065762","citation_count":6,"is_preprint":false},{"pmid":"36617784","id":"PMC_36617784","title":"Identification of TAC1 Associated with Alzheimer's Disease Using a Robust Rank Aggregation Approach.","date":"2023","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/36617784","citation_count":5,"is_preprint":false},{"pmid":"26072188","id":"PMC_26072188","title":"Liquid chromatography-electrospray linear ion trap mass spectrometry analysis of targeted neuropeptides in Tac1(-/-) mouse spinal cords reveals significant lower concentration of opioid peptides.","date":"2015","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/26072188","citation_count":5,"is_preprint":false},{"pmid":"34840225","id":"PMC_34840225","title":"Tac2-N Promotes Glioma Proliferation and Indicates Poor Clinical Outcomes.","date":"2021","source":"The Tohoku journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34840225","citation_count":4,"is_preprint":false},{"pmid":"38164144","id":"PMC_38164144","title":"The plasticity of neuropeptide Y-Y1 receptor system on Tac2 neurons contributes to mechanical hyperknesis during chronic itch.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/38164144","citation_count":4,"is_preprint":false},{"pmid":"37502396","id":"PMC_37502396","title":"Molecular dissection studies of TAC1, a transcription activator of Candida drug resistance genes of the human pathogenic fungus Candida albicans.","date":"2023","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37502396","citation_count":4,"is_preprint":false},{"pmid":"29721500","id":"PMC_29721500","title":"Antioxidant Enzyme Activities and Secondary Metabolite Profiling of Oil Palm Seedlings Treated with Combination of NPK Fertilizers Infected with Ganoderma boninense.","date":"2018","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/29721500","citation_count":4,"is_preprint":false},{"pmid":"38770776","id":"PMC_38770776","title":"The TAC1 Gene in Candida albicans: Structure, Function, and Role in Azole Resistance: A Mini-Review.","date":"2024","source":"Microbial drug resistance (Larchmont, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/38770776","citation_count":3,"is_preprint":false},{"pmid":"40052456","id":"PMC_40052456","title":"Precise tiller angle control by manipulating TAC1 expression in rice.","date":"2025","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/40052456","citation_count":3,"is_preprint":false},{"pmid":"25746346","id":"PMC_25746346","title":"Acute phase cytokines, TAC1, and toll-like receptor4 mRNA expression and health associated with group size in veal calves.","date":"2015","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/25746346","citation_count":3,"is_preprint":false},{"pmid":"38227710","id":"PMC_38227710","title":"Genetic variants in the TAC1 transcriptional regulatory region affect on trainability and excitability levels in Belgian Malinois dogs.","date":"2024","source":"Veterinary medicine and science","url":"https://pubmed.ncbi.nlm.nih.gov/38227710","citation_count":3,"is_preprint":false},{"pmid":"20217335","id":"PMC_20217335","title":"Acute morphine effects on respiratory activity in mice with target deletion of the tachykinin 1 gene (Tac1-/-).","date":"2010","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/20217335","citation_count":3,"is_preprint":false},{"pmid":"39109723","id":"PMC_39109723","title":"NPK fertilization modulates enzyme activity and mitigates the impacts of salinity on West Indian cherry.","date":"2024","source":"Brazilian journal of biology = Revista brasleira de biologia","url":"https://pubmed.ncbi.nlm.nih.gov/39109723","citation_count":2,"is_preprint":false},{"pmid":"37296204","id":"PMC_37296204","title":"The Caenorhabditis elegans Shugoshin regulates TAC-1 in cilia.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37296204","citation_count":2,"is_preprint":false},{"pmid":"38945468","id":"PMC_38945468","title":"Analgesic and anti-inflammatory activities of NPK 500 capsules, a Cassia sieberiana DC. - Based herbal analgesic medicine used to treat dysmenorrhea and peptic ulcer, is mediated through the inhibition of PGE2 and iNOS.","date":"2024","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38945468","citation_count":2,"is_preprint":false},{"pmid":"39415118","id":"PMC_39415118","title":"Effects of mineral fertilization (NPK) on combined high temperature and ozone damage in rice.","date":"2024","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/39415118","citation_count":2,"is_preprint":false},{"pmid":"39914640","id":"PMC_39914640","title":"Tac1-expressing neurons in the central amygdala predominantly mediate histamine-induced itch by receiving inputs from parabrachial Tac1-expressing neurons.","date":"2025","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/39914640","citation_count":2,"is_preprint":false},{"pmid":"38392994","id":"PMC_38392994","title":"Metabolomics Reveals the Effects of Nitrogen/Phosphorus/Potassium (NPK) Fertilizer Levels on Cucumber Fruit Raised in Different Nutrient Soils.","date":"2024","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/38392994","citation_count":2,"is_preprint":false},{"pmid":"22629204","id":"PMC_22629204","title":"Effect of NPK fertilizer on chemical composition of pumpkin (Cucurbita pepo Linn.) seeds.","date":"2012","source":"TheScientificWorldJournal","url":"https://pubmed.ncbi.nlm.nih.gov/22629204","citation_count":2,"is_preprint":false},{"pmid":"2555655","id":"PMC_2555655","title":"General characteristics and viral susceptibility of a newborn pig kidney (NPK) continuous culture.","date":"1989","source":"Microbiologica","url":"https://pubmed.ncbi.nlm.nih.gov/2555655","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52627,"output_tokens":8481,"usd":0.142548,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18352,"output_tokens":2890,"usd":0.082005,"stage2_stop_reason":"end_turn"},"total_usd":0.224553,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"TAC-1 (C. elegans TACC protein) physically interacts with ZYG-9 (XMAP215 family MAP) both in vitro and in vivo, and the two proteins mutually stabilize each other; TAC-1 centrosomal localization requires gamma-tubulin and Aurora-A kinase AIR-1 activity; loss of TAC-1 results in defective microtubule assembly as measured by FRAP.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro binding assay, FRAP-based microtubule dynamics assay, RNAi knockdown, live imaging of GFP-TAC-1\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal in vitro and in vivo interaction, FRAP functional assay, replicated across three independent labs in the same year (PMIDs 12956950, 12956951, 12956952)\",\n      \"pmids\": [\"12956950\", \"12956951\", \"12956952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TAC-1 depletion (RNAi) in C. elegans embryos produces very short centrosomal microtubules and short spindles without reducing alpha-tubulin intensity near centrosomes, indicating microtubule nucleation is intact but elongation/stabilization is impaired; TAC-1 and ZYG-9 are mutually dependent for centrosomal localization.\",\n      \"method\": \"RNAi, immunofluorescence, alpha-tubulin staining\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently in three labs, multiple orthogonal methods\",\n      \"pmids\": [\"12956951\", \"12956952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In C. elegans, TAC-1 physically interacts with ZYG-8 (doublecortin domain protein) through ZYG-8's doublecortin domain; TAC-1 and ZYG-8 form a complex that does not contain ZYG-9 in vivo; TAC-1 is required for correct ZYG-9 centrosomal enrichment; the ZYG-9-TAC-1 complex is required for correct anaphase spindle positioning.\",\n      \"method\": \"Co-immunoprecipitation, temperature-sensitive allele analysis, genetic epistasis, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"17666432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, Shugoshin SGO-1 binds TAC-1 (TACC protein) and constrains TAC-1 to the ciliary basal body via the transition zone; TAC-1 activity must be maintained below a threshold at the ciliary base for correct cilia function, and SGO-1 participates in this regulation.\",\n      \"method\": \"Yeast two-hybrid / binding assay, genetic epistasis, immunofluorescence, cilia functional assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, genetic and localization evidence but limited biochemical reconstitution details in abstract\",\n      \"pmids\": [\"37296204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Targeted deletion of the Tac1 gene (encoding substance P and neurokinin A) in mice diminishes anxiety- and depression-related behaviors, establishing that Tac1-encoded tachykinins are required for normal fear and stress responses.\",\n      \"method\": \"Tac1 knockout mice, behavioral paradigms (forced-swim, tail-suspension, open-field, elevated zero-maze, social interaction)\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined behavioral phenotypes across multiple paradigms, replicated across multiple behavioral tests\",\n      \"pmids\": [\"12427862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tac1-expressing glutamatergic neurons in the lateral/ventrolateral PAG facilitate the itch-scratching cycle via descending regulation; ablation or suppression of these neurons decreases itch-induced scratching; their activation-evoked scratching is suppressed by ablation of spinal GRPR neurons.\",\n      \"method\": \"Chemogenetics (DREADDs), optogenetics, neuron ablation, fiber photometry, behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal circuit-manipulation methods (chemogenetics, ablation, optogenetics) with defined behavioral readouts in single rigorous study\",\n      \"pmids\": [\"30554781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tac2 gene (encoding NkB) expressed in centromedial amygdala (CeM) neurons is required for fear memory consolidation; NkB and its receptor Nk3R mediate this effect; increased Tac2 expression or lentiviral CeA overexpression enhances fear consolidation, blocked by Nk3R antagonist osanetant; silencing Tac2-expressing neurons via DREADDs impairs fear consolidation.\",\n      \"method\": \"Lentiviral overexpression, DREADD-based silencing, pharmacological Nk3R antagonism, fear conditioning behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (gain-of-function, loss-of-function, pharmacology) with defined behavioral readout in single rigorous study\",\n      \"pmids\": [\"24976214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In vivo optogenetic stimulation of CeA Tac2-expressing neurons (ChR2 knockin mice) during fear acquisition enhanced fear memory consolidation and drove action potential firing in vitro; Tac2-CeA neurons co-express striatal-enriched protein tyrosine phosphatase (STEP), which may regulate Nk3R signaling.\",\n      \"method\": \"Optogenetics (ChR2 in Tac2-Cre mice), in vitro electrophysiology, immunofluorescence\",\n      \"journal\": \"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — optogenetics with behavioral readout and electrophysiology, single lab\",\n      \"pmids\": [\"27238620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Chronic social isolation stress (2 weeks) in mice induces brain-wide upregulation of Tac2/NkB; systemic Nk3R antagonist prevents virtually all behavioral effects of chronic social isolation; enhancing NkB expression and release in group-housed mice phenocopies social isolation stress; dissociable region-specific requirements for Tac2 peptide and Nk3R in different behavioral changes.\",\n      \"method\": \"Viral vector-mediated NkB overexpression, pharmacological Nk3R antagonism, brain-wide circuit manipulation (chemogenetics/DREADDs), behavioral assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal gain- and loss-of-function methods across brain regions with rigorous behavioral readouts in single high-impact study\",\n      \"pmids\": [\"29775595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sex differences exist in Tac2 pathway regulation of fear memory consolidation: CeA-Tac2 antagonism impairs fear memory in males but enhances it in females; CeA-testosterone mediates Tac2 effects in males, CeA-estradiol in females; Akt/GSK3β/β-Catenin signaling mediates the sex-differential Tac2 pathway regulation.\",\n      \"method\": \"Pharmacogenetic inhibition (DREADDs), intracranial hormone manipulation, western blotting of signaling proteins, fear conditioning\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemogenetics, pharmacology, and signaling pathway analysis in single lab with multiple methods\",\n      \"pmids\": [\"33941789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tac1-expressing neurons in the nucleus accumbens (NAc) lateral shell project to ventral pallidum and contribute to stress-induced anhedonia-like behavior; selective inhibition and activation of Tac1-NAc neurons bidirectionally modulate stress susceptibility; inhibition of neurokinin 1 receptor promotes susceptibility to social stress.\",\n      \"method\": \"Chemogenetics (DREADDs), optogenetics, circuit tracing, behavioral assays (sucrose preference, social defeat)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional chemogenetic manipulation with circuit tracing, single lab\",\n      \"pmids\": [\"33147466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tac1 neurons in the NAc medial shell project to the lateral hypothalamic area (LH); the NAc-Tac1→LH pathway contributes to avoidance responses to aversive stimuli; medial prefrontal cortex sends excitatory inputs to NAc-Tac1 neurons regulating avoidance.\",\n      \"method\": \"Chemogenetics, optogenetic circuit dissection, anterograde/retrograde tracing, behavioral assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — optogenetic pathway dissection and chemogenetics in single lab\",\n      \"pmids\": [\"36901777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"REST (RE-1 silencing transcription factor) binds the 5' UTR of the TAC1 promoter and suppresses TAC1 expression; REST expression in breast cancer cells is inversely proportional to aggressiveness; REST knockdown increases TAC1 expression, proliferation, and migration in low-metastatic cells; ectopic REST in aggressive cells reduces these parameters.\",\n      \"method\": \"Reporter gene assays, western blot, RT-PCR, REST knockdown/overexpression, cell migration assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter binding combined with loss/gain-of-function in single lab with multiple readouts\",\n      \"pmids\": [\"19246391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"REST and NFκB synergistically repress TAC1 transcription in human mesenchymal stem cells; two REST-binding sites are adjacent to one NFκB site within exon 1 of the TAC1 promoter; ChIP and mutagenesis confirmed both factors cooperate for repression in neurogenic and cytokine-stimulated conditions.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter gene mutagenesis, loss-of-function (siRNA/dominant negative), transcription factor mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and mutagenesis in single lab with multiple functional assays\",\n      \"pmids\": [\"17709376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TAC1 promoter requires synergy with a remote enhancer element (ECR2) to respond to MEK/ERK (MAPK) signaling in sensory neurons; antagonism of the MEK pathway blocks noxious stimulation-driven TAC1 enhancer-promoter synergy; capsaicin induction involves a non-cell-autonomous mechanism in larger diameter neurons.\",\n      \"method\": \"Comparative genomics (ECR identification), transgenic mouse reporter assays, pharmacological MEK inhibition, primary sensory neuron culture, capsaicin stimulation\",\n      \"journal\": \"Neuro-Signals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic reporters combined with pharmacological inhibition in primary cells, single lab\",\n      \"pmids\": [\"21160161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NK1 receptor is expressed in all SP-expressing sensory neurons after capsaicin induction; an NK1 agonist activates both SP expression and the TAC1 ECR1 enhancer-promoter in larger diameter neurons, demonstrating an autocrine loop controlling TAC1 promoter activity in sensory neurons.\",\n      \"method\": \"Reporter gene assays, immunofluorescence, pharmacological NK1 agonist treatment, primary sensory neuron culture\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay plus pharmacological validation in primary neurons, single lab\",\n      \"pmids\": [\"21294877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"During MSC-to-neuron differentiation, CRE1 and CRE2/AP-1 sites in the TAC1 promoter are activated sequentially (days 6 and 12); decrease of REST activates JNK, which activates ATF-2 and AP-1 to bind CRE1 and CRE2/AP-1 respectively; JNK inhibition blocks TAC1 induction; transplanted JNK-pathway-active MSCs improve spinal cord injury in zebrafish.\",\n      \"method\": \"Reporter gene assays with CRE mutants, PKA/JNK inhibitors, ChIP, ectopic REST expression, in vivo zebrafish SCI model\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, mutagenesis, pharmacological inhibition) in single lab\",\n      \"pmids\": [\"21671725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SDF-1α regulates TAC1 expression in bone marrow stromal cells via NF-κB; at high SDF-1α levels (≥50 ng/mL) NF-κB activation mediates repression of TAC1 within exon 1; substance P produced downstream does not regulate SDF-1α production (negative finding); substance P signals through NK1 (not NK2) receptor to stimulate hematopoiesis.\",\n      \"method\": \"Reporter gene assays, gel shift (EMSA), NF-κB mutant IκB transfection, Northern blot, ELISA, long-term culture-initiating cell assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, dominant-negative functional assay, and multiple readouts in single lab\",\n      \"pmids\": [\"17277111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In non-tumorigenic breast cells, SDF-1α at low concentrations activates TAC1 via CRE sites through a non-canonical Gαi2-PI3K-PKCζ-p38-ERK pathway to phosphorylate CREB, distinct from the cAMP-PKA pathway used in bone marrow stromal cells.\",\n      \"method\": \"Reporter gene assays with CRE mutants, ICER co-transfection, western blot with pathway inhibitors, signaling inhibitor panel\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors with reporter assays, single lab\",\n      \"pmids\": [\"18316470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MeCP2 binds directly to the TAC1 promoter in HEK cells as shown by ChIP; antiepileptic drug (valproic acid) treatment alters MeCP2 binding to TAC1 promoter; TAC1 promoter CpG hypermethylation correlates with reduced TAC1 expression in autism and seizure disorder.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), DNA methylation profiling, Sequenom EpiTYPER validation, qRT-PCR\",\n      \"journal\": \"Journal of neurodevelopmental disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP in a single cell-line model with corroborating methylation profiling, single lab\",\n      \"pmids\": [\"23759142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Post-transcriptional regulation of Tac1 mRNA in bone marrow stroma involves RNA-binding proteins (with differential binding kinetics for stimulatory vs. inhibitory cytokines) and cytokine-induced miRNAs that interact with the 3' UTR of Tac1 mRNA.\",\n      \"method\": \"RNA electrophoretic mobility shift assay (RNA-EMSA), miRNA detection/interaction assays\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RNA-EMSA and miRNA detection, no identity of specific binding proteins/miRNAs, single lab\",\n      \"pmids\": [\"18061399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tac1-encoded tachykinins (substance P and neurokinin A) are required for morphine-induced respiratory depression and the aversive aspect of opioid withdrawal; in Tac1-/- mice morphine analgesia is enhanced and behavioral sensitization (addiction mechanism) is reduced.\",\n      \"method\": \"Tac1 knockout mice, morphine analgesic assays, naloxone-precipitated withdrawal, behavioral sensitization, conditioned place preference\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple behavioral readouts across analgesic, respiratory, and addiction paradigms, single lab\",\n      \"pmids\": [\"20590634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tac1 knockout male mice show delayed puberty, decreased Pdyn and Nos1 expression, and elevated GnRH levels; kisspeptin receptor (Kiss1R) and substance P receptor (NK1R) heterodimerize, suggesting SP tone alters GnRH neuron responsiveness to kisspeptin; Tac1-/- mice show decreased LH response to central kisspeptin and senktide administration despite intact GnRH neuron stimulation.\",\n      \"method\": \"Tac1 knockout mice, RT-qPCR, receptor heterodimerization assay (co-IP/FRET), electrophysiology of arcuate Kiss1 neurons, LH ELISA\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor heterodimerization assay plus KO phenotype and electrophysiology, single lab\",\n      \"pmids\": [\"28444173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TAC1-encoded substance P and neurokinin A maintain basal cutaneous microcirculation; Tac1-/- mice show significantly lower basal postoperative skin microcirculation but mustard oil-induced neurogenic vasodilation is unaffected, while motor coordination is impaired in Tac1-/- mice.\",\n      \"method\": \"Tac1 knockout mice, laser Doppler imaging, Rota-Rod test, dynamic plantar aesthesiometry\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined physiological readouts, multiple functional measurements, single lab\",\n      \"pmids\": [\"23499760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tac1 knockout nociceptors display disrupted encoding of tonic suprathreshold mechanical stimuli and fail to develop mechanical sensitization after injury; Tac1-/- mice show reduced paw edema, hypersensitivity, and weight-bearing deficits after incision, and their nociceptors lack post-incision electrical hyperexcitability, despite normal CGRP upregulation.\",\n      \"method\": \"Tac1 knockout mice, in vivo electrophysiology of primary afferents, behavioral nociception assays, immunofluorescence\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo afferent electrophysiology combined with behavioral and immunohistochemical validation in KO model\",\n      \"pmids\": [\"31012376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Absence of Tac1-encoded tachykinins (Tac1-/- mice) is associated with significantly lower spinal cord concentrations of opioid peptides endomorphin-2, leucine-enkephalin, and dynorphin A (Dyn A ~3-fold lower), suggesting tachykinin system supports endogenous opioid tone.\",\n      \"method\": \"HPLC-linear ion trap mass spectrometry (LC-MS/MRM) quantification of spinal cord neuropeptides in Tac1-/- vs wild-type mice\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous mass spectrometric quantification but single lab, single method\",\n      \"pmids\": [\"26072188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tac1 ablation in mice produces a lean phenotype with reduced food intake, altered circadian feeding rhythm (disrupted clock gene Cry1/2, Per1/2 expression in SCN, MBH, and liver), increased proopiomelanocortin (POMC) expression in MBH, resistance to diet-induced obesity, and improved glucose tolerance; Tac1 controls energy balance through the melanocortin system.\",\n      \"method\": \"Tac1 knockout mice, metabolic cage analysis, RT-qPCR, high-fat diet challenge, glucose/insulin tolerance tests, brown adipose tissue thermogenic assay\",\n      \"journal\": \"International journal of obesity (2005)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple metabolic and molecular readouts, single lab\",\n      \"pmids\": [\"28775376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Candida albicans, hyperactivated Tac1 (by gain-of-function mutations or xenobiotics) facilitates recruitment of the Mediator coactivator complex to the CDR1 promoter; CDR1 activation and azole resistance depend on the Tac1 C-terminal transcriptional activation domain (TAD) and Mediator tail module subunits; Tac1 hyperactivation correlates with Mediator-dependent Tac1 phosphorylation; the Tac1 middle region negatively regulates the TAD.\",\n      \"method\": \"Promoter ChIP of Mediator subunits, transcriptional activation domain mapping, Mediator tail subunit deletion strains, azole susceptibility testing\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP of coactivator recruitment combined with domain-deletion functional analysis, single lab\",\n      \"pmids\": [\"28807920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. albicans Tac1, the N-terminal DNA binding domain (DBD) interacts with the Drug Responsive Element (DRE) in CDR1/CDR2 promoters; the C-terminal Acidic Activation Domain (AAD) interacts with TATA box binding protein (TBP); the Middle Homology Region (MHR) acts as a xenobiotic binding domain (XBD) important for drug resistance.\",\n      \"method\": \"Domain deletion/truncation analysis, reporter gene assays, protein-protein interaction assays (TBP binding), DRE binding assays\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain dissection with functional assays for DNA and protein binding, single lab\",\n      \"pmids\": [\"37502396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C. albicans Tac1 and Znc1 are functionally activated by farnesol (quorum-sensing molecule) and together bind the CDR1 promoter to upregulate CDR1; CDR1 expression then facilitates farnesol efflux; Tac1 and Znc1 have overlapping but non-identical regulons.\",\n      \"method\": \"Tac1/Znc1 deletion strains, promoter-ChIP, CDR1 reporter assays, farnesol growth/efflux assays, RNA-seq\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, KO strains, and functional efflux assays with RNA-seq, single lab\",\n      \"pmids\": [\"30104273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Candida parapsilosis, gain-of-function mutation CpTac1-G650E causes 8-fold increase in fluconazole MIC and overexpression of CpCDR1, CpCDR1B, and CpCDR1C; correction of this mutation reduces MIC 16-fold; disruption of CDR1/CDR1B/CDR1C together reduces MIC 4-fold, establishing CpTac1 as a direct regulator of efflux pump-mediated triazole resistance.\",\n      \"method\": \"CRISPR-Cas9 precise editing (introduction and correction of CpTAC1 mutation), RNA-seq, RT-qPCR, broth microdilution susceptibility testing\",\n      \"journal\": \"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — precise genome editing (introduction and reversion), RNA-seq, and susceptibility testing in single rigorous study\",\n      \"pmids\": [\"37666448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TAC1 is expressed in the sheep pars tuberalis (PT) and strongly activated by long photoperiod; TAC1-encoded peptides (substance P and neurokinin A) act as prolactin secretagogues on primary pituitary cells, making TAC1 a candidate for the PT-expressed 'tuberalin' seasonal hormone regulator.\",\n      \"method\": \"Microarray, in situ hybridization, primary pituitary cell prolactin secretion assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional prolactin secretion assay on primary cells combined with expression mapping, single lab\",\n      \"pmids\": [\"20434341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In indica rice, fine-tuning TAC1 expression levels via CRISPR-Cas9 editing of upstream and downstream non-coding regions produces gradient tiller angle changes proportional to TAC1 expression levels, with no effect on other agronomic traits; TAC1 is conserved across species including fruit trees.\",\n      \"method\": \"Multiplex CRISPR-Cas9 editing, RT-qPCR expression quantification, phenotypic analysis of homozygous allelic lines\",\n      \"journal\": \"Journal of integrative plant biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — plant ortholog (rice TAC1) not the human/mammalian TAC1 gene; included for completeness but represents a symbol collision with a plant gene\",\n      \"pmids\": [\"40052456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the spinal cord dorsal horn, Tac2-expressing neurons receive direct inhibitory input from Npy neurons; during chronic itch, Y1R expression on Tac2 neurons is reduced and NPY-Y1R inhibitory regulation of Tac2 neurons is diminished, contributing to mechanical hyperknesis.\",\n      \"method\": \"Rabies virus circuit tracing, chemogenetics, immunofluorescence, electrophysiology, transgenic mice\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — circuit tracing combined with chemogenetic manipulation and electrophysiology, single lab\",\n      \"pmids\": [\"38164144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PBNTac1 neurons form close synaptic connections with CeATac1 neurons; activation of the PBNTac1→CeA pathway increases scratching in histamine-induced itch but not chloroquine-induced itch; inhibition of this pathway decreases histamine-induced scratching, defining a modality-specific itch circuit.\",\n      \"method\": \"Fiber photometry, chemogenetics (DREADDs), immunohistochemistry, behavioral itch assays\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple circuit methods with behavioral readouts, single lab\",\n      \"pmids\": [\"39914640\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human/mammalian TAC1 encodes the tachykinin neuropeptides substance P and neurokinin A, which act through NK1R (and NK2R) to modulate diverse processes including nociception, fear memory consolidation (via NkB/Tac2-related circuits in the amygdala), itch-scratching cycles (via Tac1+ PAG and amygdala neurons projecting to spinal GRPR neurons), stress-induced anhedonia (via NAc→ventral pallidum Tac1 circuits), circadian feeding and energy balance (through the melanocortin/POMC system), and reproductive function (by modulating GnRH neuron responsiveness through NK1R-Kiss1R heterodimerization); TAC1 transcription is repressed by REST and NFκB cooperatively, activated downstream of SDF-1α through CRE sites via JNK/ATF-2/AP-1 and a non-canonical Gαi2-PI3K-PKCζ-ERK pathway, and is regulated by MeCP2 binding and promoter methylation; in the fungal pathogen Candida albicans, the unrelated TAC1 gene encodes a zinc-cluster transcription factor whose gain-of-function mutations hyperactivate CDR1/CDR2 efflux pump expression via Mediator complex recruitment, conferring azole resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The TAC1 symbol in this corpus resolves to at least three biologically unrelated genes, and the mammalian TAC1 entries describe a tachykinin neuropeptide precursor. In mammals, TAC1 encodes substance P and neurokinin A, neuropeptides whose loss diminishes anxiety- and depression-related behavior and disrupts stress and fear responses [#4]. These peptides act largely through NK1R: Tac1-expressing neurons drive defined circuits including a lateral/ventrolateral PAG pathway that facilitates the itch-scratching cycle via spinal GRPR neurons [#5], a nucleus accumbens shell projection to ventral pallidum that bidirectionally controls stress-induced anhedonia [#10], and an accumbens medial-shell projection to lateral hypothalamus governing aversive avoidance [#11]. TAC1 tachykinins are required for injury-induced nociceptor mechanical sensitization and hyperexcitability [#24], for morphine-induced respiratory depression and opioid withdrawal aversion [#21], and they support endogenous spinal opioid peptide tone [#25]. Beyond the nervous system, TAC1 peptides maintain basal cutaneous microcirculation [#23], modulate puberty and GnRH-neuron responsiveness to kisspeptin via NK1R-Kiss1R heterodimerization [#22], control energy balance and circadian feeding through the melanocortin/POMC system [#26], and act as prolactin secretagogues in the seasonally regulated pars tuberalis [#31]. TAC1 transcription is repressed by REST, which cooperates synergistically with NF\\u03baB at sites within exon 1 [#12, #13], and is activated downstream of SDF-1\\u03b1 through CRE/CREB signaling using distinct pathways in different cell types\\u2014cAMP-independent G\\u03b1i2-PI3K-PKC\\u03b6-ERK signaling in breast cells [#18]\\u2014together with JNK/ATF-2/AP-1 input and enhancer (ECR) synergy in differentiating and sensory neurons [#14, #16], plus MeCP2 binding and promoter CpG methylation [#19]. Separately and unrelated to the neuropeptide gene, the C. elegans TAC-1 (a TACC-family microtubule-associated protein) and the Candida/Candida parapsilosis Tac1 (a zinc-cluster transcription factor) and a plant TAC1 (tiller angle control) appear in this corpus as symbol collisions describing entirely distinct proteins.\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing whether TAC1-encoded tachykinins are dispensable for affective behavior, genetic ablation defined a required role in normal fear and stress responses.\",\n      \"evidence\": \"Tac1 knockout mice across multiple anxiety/depression behavioral paradigms\",\n      \"pmids\": [\"12427862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which peptide (SP vs NkA) or which receptor mediates each behavior\", \"Circuit/region of action not localized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"To define the receptor-level and pathway logic of TAC1 transcription, studies showed REST and SDF-1\\u03b1 inputs converge on the promoter and that tachykinins regulate opioid-related physiology.\",\n      \"evidence\": \"Reporter assays, EMSA, ChIP, Tac1-KO opioid/withdrawal behavioral assays in stromal/sensory cells and mice\",\n      \"pmids\": [\"19246391\", \"17709376\", \"17277111\", \"18316470\", \"20590634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type specificity of the non-canonical G\\u03b1i2-PI3K-PKC\\u03b6-ERK pathway not generalized\", \"Endogenous miRNA/RNA-binding regulators of Tac1 mRNA not identified at molecular identity level\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"To explain stimulus-driven TAC1 induction in sensory neurons, work showed promoter activity requires remote enhancer (ECR) synergy with MEK/ERK and an autocrine NK1 feedback loop.\",\n      \"evidence\": \"Transgenic reporter assays, MEK/JNK inhibitors, NK1 agonist treatment, primary sensory neuron culture\",\n      \"pmids\": [\"21160161\", \"21294877\", \"21671725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-cell-autonomous induction mechanism in large-diameter neurons not fully defined\", \"In vivo relevance of the autocrine loop to nociception untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining systemic and developmental roles, Tac1 ablation revealed contributions to puberty/GnRH responsiveness via NK1R-Kiss1R heterodimerization, energy balance through the melanocortin system, and cutaneous microcirculation.\",\n      \"evidence\": \"Tac1-KO mice with receptor heterodimerization assays, metabolic cage/glucose tests, laser Doppler imaging, prolactin secretion assays\",\n      \"pmids\": [\"28444173\", \"28775376\", \"23499760\", \"20434341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural confirmation of NK1R-Kiss1R heterodimer signaling consequences limited\", \"Circadian feeding effect mechanism (clock gene regulation) not causally dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"To map where TAC1 neurons act, circuit-level dissection defined PAG, NAc-shell, and NAc-medial-shell Tac1 projections controlling itch, anhedonia, and avoidance, respectively.\",\n      \"evidence\": \"Chemogenetics, optogenetics, anterograde/retrograde tracing, behavioral assays in mice\",\n      \"pmids\": [\"30554781\", \"33147466\", \"36901777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TAC1 peptide release (vs fast neurotransmission) drives each circuit effect is unresolved\", \"Receptor identity at each downstream node not uniformly defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"To test TAC1's role in peripheral pain encoding, knockout afferent recordings showed tachykinins are required for injury-induced mechanical sensitization and nociceptor hyperexcitability.\",\n      \"evidence\": \"In vivo primary afferent electrophysiology and behavioral nociception in Tac1-KO mice\",\n      \"pmids\": [\"31012376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target downstream of SP/NkA in sensitized afferents not identified\", \"Relationship to CGRP (unchanged) signaling not mechanistically resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor-coupled signaling cascades and cell-type-specific circuit logic linking TAC1 peptide release to each behavioral and physiological outcome remain incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking SP vs NkA, NK1R vs NK2R, to specific phenotypes\", \"Corpus is contaminated by unrelated TAC-1/Tac1 genes (C. elegans TACC protein, fungal zinc-cluster transcription factor, plant tiller-angle gene) that do not inform mammalian TAC1 function\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [22, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [25, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 5, 10, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [22, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NK1R\", \"Kiss1R\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}