Affinage

SHOX2

Short stature homeobox protein 2 · UniProt O60902

Length
331 aa
Mass
35.0 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHOX2 is a paired-related homeodomain transcription factor that serves as a master regulator of sinoatrial node pacemaker identity, proximal limb osteogenesis, somatosensory neuron specification, and spinal locomotor rhythm generation. In the sinoatrial node, SHOX2 represses Nkx2.5 — requiring ERK1/2-mediated phosphorylation at Ser92/Ser110 for DNA binding — directly activates Isl1, and sustains BMP4 signaling to establish and maintain pacemaker cell fate; SHOX2 also physically interacts with Nkx2.5 protein and shares genome-wide co-occupancy with Nkx2.5 and Tbx5, antagonizing the working-myocardial gene program (PMID:17372176, PMID:24847033, PMID:23455426, PMID:26138475, PMID:23767866). In the proximal limb and palate, SHOX2 binds cis-regulatory enhancers co-occupied by Hox-TALE (Pbx/Meis) factors, acting as a lineage-autonomous repressor to control chondrocyte maturation through Runx2/Runx3/Ihh and to regulate accessible chromatin at skeletogenic loci (PMID:17481601, PMID:27287812, PMID:31649032). Loss-of-function mutations in SHOX2 cause familial atrial fibrillation and sinus node dysfunction (PMID:30443179, PMID:27138930).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 Medium

    Cloning of SHOX2 (SHOT) established it as a paired-related homeodomain transcription factor with two isoforms and a spatially restricted embryonic expression pattern in the sinus venosus, brain, palate, and limbs, framing its candidate developmental roles.

    Evidence cDNA cloning and in situ hybridization on staged mouse embryos

    PMID:9482898

    Open questions at the time
    • No functional data; expression pattern alone does not establish necessity
    • Transcriptional targets unknown
  2. 2007 High

    Gene knockout revealed that SHOX2 is essential for both sinoatrial node formation and proximal limb chondrocyte maturation, defining its two major developmental territories and identifying downstream effectors (Nkx2.5 derepression in SAN; Runx2/Runx3/Ihh downregulation and ectopic BMP4 in limb).

    Evidence Targeted Shox2 knockout mice and zebrafish morpholino knockdown with ISH and functional assays; separate KO analysis of limb cartilage with BMP4 rescue

    PMID:17372176 PMID:17481601

    Open questions at the time
    • Direct DNA binding to Nkx2.5 promoter not yet shown
    • Whether SHOX2 acts as activator or repressor at individual loci not resolved
  3. 2008 Medium

    Conditional ablation in cranial neural crest cells extended SHOX2's osteogenic role to the temporomandibular joint, demonstrating a broader requirement in craniofacial skeletogenesis beyond the limb.

    Evidence Wnt1-Cre conditional knockout with histology and cell proliferation assays

    PMID:18514492

    Open questions at the time
    • Specific transcriptional targets in TMJ not identified
    • Mechanism of ankylosis not molecularly resolved
  4. 2011 High

    Three advances clarified SHOX2's mechanistic repertoire: (1) human SHOX functionally replaces mouse Shox2 in the SAN, proving conserved Nkx2.5 repression; (2) Shox2 specifies TrkB+ mechanoreceptive sensory neurons downstream of Runx3 suppression; (3) Shox2 is required for multi-tissue development including axonal guidance in the proximal forelimb.

    Evidence SHOX knock-in rescue mice with reporter assays; conditional KO with behavioral light-touch assay and genetic epistasis (Runx3−/−;Bax−/−); microarray and nerve phenotype analysis in Shox2 KO

    PMID:21156168 PMID:21454626 PMID:22103411

    Open questions at the time
    • Mechanism by which Shox2 enables TrkB expression not resolved
    • Axonal guidance targets of Shox2 not identified
  5. 2013 High

    Multiple studies established the direct transcriptional target repertoire and downstream signaling of SHOX2 in the SAN: Isl1 was identified as a direct target via binding to ISL1 intron 2 (with zebrafish rescue), BMP4 was shown to be a key downstream effector whose exogenous addition rescues pacemaker function in Shox2-null embryoid bodies, and Shox2-expressing spinal interneurons were independently demonstrated to be rhythm-generating components of locomotor circuits.

    Evidence EMSA and luciferase reporter assays with zebrafish rescue for Isl1; embryoid body differentiation with BMP4 rescue/Noggin inhibition; optogenetic silencing and connectivity mapping in transgenic mice for locomotor INs

    PMID:23455426 PMID:23767866 PMID:24267650

    Open questions at the time
    • Whether Shox2 directly binds BMP4 regulatory elements unknown
    • Identity of rhythm-generating partners of Shox2 INs incomplete
  6. 2014 High

    ERK1/2-dependent phosphorylation at Ser92/Ser110 was established as essential for SHOX2 DNA binding and Nkx2.5 repression, linking upstream signaling to SHOX2 transcriptional activity; additional studies revealed SHOX2 dimerization and cooperation with SOX5/SOX6 in activating ACAN, and Tbx4 as an upstream activator of Shox2 in limb development.

    Evidence Yeast two-hybrid, co-IP, in vitro kinase assay, phospho-mutant transgenic rescue in mice; luciferase/Y2H/Co-IP for SOX interaction; EMSA for Tbx4 binding to Shox2 promoter

    PMID:24347445 PMID:24421874 PMID:24847033

    Open questions at the time
    • Phosphatase (PP2A-B56δ) regulation kinetics and tissue specificity not resolved
    • Whether SOX5/6 cooperation is SAN-relevant unknown
  7. 2014 Medium

    SHOX2 was found to promote EMT in breast cancer by transcriptionally upregulating TGFβ receptor I, and to regulate cerebellar Purkinje cell Shh expression controlling granule cell precursor differentiation, broadening SHOX2 biology beyond the SAN and limb.

    Evidence miR-375 overexpression/rescue and TβRI inhibitor experiments in breast cancer cells; Nestin-Cre conditional KO with ISH and behavioral motor assays

    PMID:24746361 PMID:25528224

    Open questions at the time
    • Direct binding of SHOX2 to TβRI promoter not demonstrated
    • Whether cerebellar Shh regulation is direct or indirect unknown
  8. 2015 High

    Genome-wide ChIP analysis demonstrated that SHOX2 physically interacts with Nkx2.5 protein and shares substantial co-occupancy with Nkx2.5 and Tbx5 across the genome, establishing SHOX2 as an antagonist of the working-myocardial transcription factor network; Nkx2.5 hypomorphism rescued Shox2-mutant SAN gene expression, confirming genetic antagonism.

    Evidence ChIP co-occupancy analysis, co-immunoprecipitation, conditional KO with electrophysiology, Nkx2.5 hypomorph epistasis

    PMID:26138475

    Open questions at the time
    • Whether SHOX2–Nkx2.5 interaction occurs on chromatin or prevents Nkx2.5 binding is unclear
    • Structural basis of interaction unknown
  9. 2016 High

    Lineage-specific conditional knockout and ChIP-Seq demonstrated that SHOX2 controls stylopod patterning specifically through the osteogenic lineage by binding cis-regulatory enhancers co-occupied by Hox-TALE factors (Pbx/Meis), acting as a repressor that antagonizes TALE-mediated repression at skeletogenic loci.

    Evidence Osteogenic lineage-specific conditional KO, ChIP-Seq for Shox2 and Pbx, RNA-Seq, transgenic enhancer assays

    PMID:27287812

    Open questions at the time
    • How SHOX2 antagonizes TALE repression mechanistically (competition vs. co-factor displacement) not resolved
    • Whether SHOX2 recruits co-activators at these enhancers unknown
  10. 2016 Medium

    Human genetic studies identified SHOX2 coding and 3'UTR variants that impair transactivation and pacemaker function, linking SHOX2 loss-of-function to atrial fibrillation and sinus node dysfunction in patients.

    Evidence Transactivation assays, zebrafish rescue, miRNA binding site validation, patient sequencing

    PMID:27138930 PMID:30443179 PMID:31354791

    Open questions at the time
    • No large-scale replication cohort for AF association
    • Genotype–phenotype correlation across different mutations incomplete
  11. 2019 High

    Multi-omic profiling of the anterior palate revealed that SHOX2 regulates chromatin accessibility at distal cis-regulatory elements in a tissue-specific manner, controlling expression of pattern specification and skeletogenic genes through H3K27ac-marked active enhancers.

    Evidence ATAC-Seq, H3K27ac ChIP-Seq, RNA-Seq, and transgenic enhancer assays in conditional KO palate tissue

    PMID:31649032

    Open questions at the time
    • Whether SHOX2 directly remodels chromatin or recruits remodelers unknown
    • Palate-specific cofactors not identified
  12. 2021 Medium

    After spinal cord injury, Shox2 locomotor interneurons retain intrinsic excitability but undergo a shift in sensory input balance and serotonergic modulation (from 5-HT7 to 5-HT2B/2C), informing how rhythm-generating circuits are reorganized after injury.

    Evidence Whole-cell patch-clamp with pharmacological receptor characterization in thoracic transection model

    PMID:34006587

    Open questions at the time
    • Whether Shox2 transcriptional activity changes after SCI unknown
    • Functional consequence for locomotor recovery not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of SHOX2's interactions with Nkx2.5 and TALE factors, the mechanism by which SHOX2 remodels chromatin accessibility, whether SHOX2 directly binds BMP4 regulatory regions, and whether oncogenic roles (TGFβRI activation, NPHP4-Hippo axis) reflect the same transcriptional mechanisms used in development.
  • No crystal or cryo-EM structure of SHOX2 homeodomain–DNA complex
  • Direct BMP4 promoter binding not tested
  • Cancer mechanisms lack in vivo genetic validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-1266738 Developmental Biology 9 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 3
Partners
ISL1NKX2-5PBX1PPP2R5DSOX5SOX6TBX4TBX5

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Shox2 is required for development of the sinus venosus myocardium including the sinoatrial nodal region; Shox2-/- mice show severe hypoplasia of the sinoatrial node and aberrant expression of connexin 40, connexin 43, and Nkx2.5 specifically within the sinoatrial nodal region, establishing Shox2 as essential for pacemaking function. Targeted gene knockout in mice, in situ hybridization, zebrafish knockdown with pacemaking functional assay Circulation High 17372176
2007 Shox2 is required for chondrocyte proliferation and maturation in the proximal limb (stylopod); loss of Shox2 causes downregulation of Runx2, Runx3, and Ihh, and enhanced/ectopic Bmp4 expression underlies Runx2 downregulation; Shox2 can act as either a transcriptional activator or repressor depending on cell type. Knockout mouse model, in situ hybridization, exogenous BMP4 application, reporter assays Developmental biology High 17481601
1998 SHOX2 (originally named SHOT) is a paired-related homeodomain transcription factor with two isoforms (SHOTa, SHOTb) sharing identical homeodomains and a C-terminal 14-amino acid motif; expression is restricted to developing sinus venosus, diencephalon, nasal capsule, palate, eyelid, and limbs in mouse embryos. cDNA cloning, in situ hybridization on staged mouse embryos, sequence/domain analysis Proceedings of the National Academy of Sciences of the United States of America Medium 9482898
2011 Shox2 represses Nkx2.5 expression to maintain sinoatrial node (SAN) cell fate; human SHOX and mouse Shox2 share similar transcriptional repressive activity on the Nkx2.5 promoter and are functionally redundant in SAN formation, as demonstrated by SHOX knock-in replacing Shox2 rescuing normal SAN development and pacemaking. Knock-in mouse model (SHOX replacing Shox2), cell culture reporter assays, physiological and histological analysis The Journal of biological chemistry High 21454626
2013 Islet1 (Isl1) is a direct transcriptional target of Shox2 in the sinoatrial node; Shox2 binds two specific sites within intron 2 of the ISL1 locus and activates Isl1 expression; Isl1 overexpression rescues the Shox2-mediated bradycardia phenotype in zebrafish. Microarray, luciferase reporter assay, EMSA, zebrafish rescue experiments, whole-mount in situ hybridization Basic research in cardiology High 23455426
2013 Spinal Shox2 interneurons (excitatory, ipsilaterally projecting) are part of the rhythm-generating kernel for locomotion; optogenetic silencing or blocking synaptic output of Shox2 INs perturbs locomotor rhythm without affecting pattern; Shox2 INs contact other Shox2 INs, commissural neurons, and motor neurons with preference for flexor motor neurons. Optogenetic silencing, transgenic mice, synaptic connectivity analysis, ablation experiments Neuron High 24267650
2014 Phosphorylation of Shox2a at Ser92 and Ser110 by ERK1/2 is required for Shox2a to bind the Nkx2.5 promoter and repress Nkx2.5 expression during sinoatrial node development; B56δ regulatory subunit of PP2A interacts with Shox2a; phosphorylation mutants fail to rescue SAN defects in Shox2 mutant mice. Yeast 2-hybrid, co-immunoprecipitation, western blot, immunohistochemistry, site-directed mutagenesis, in vitro kinase assay, transgenic mouse rescue Journal of the American Heart Association High 24847033
2015 Shox2 antagonizes the transcriptional output of Nkx2.5 in the pulmonary vein myocardium and SAN to determine pacemaker cell fate; Shox2 interacts directly with Nkx2.5 protein and shows substantial genome-wide co-occupancy with Nkx2.5 and Tbx5; Shox2 deletion in the Nkx2-5+ domain of the SAN causes sick sinus syndrome; Nkx2.5 hypomorphism rescues Shox2 mutant SAN gene expression. Conditional knockout, electrophysiology of explanted Shox2+ cells, genome-wide ChIP co-occupancy analysis, genetic epistasis (Nkx2.5 hypomorph rescue), co-immunoprecipitation Development (Cambridge, England) High 26138475
2008 Conditional inactivation of Shox2 in cranial neural crest-derived cells causes TMJ dysplasia, including dysplasia of condyle and glenoid fossa and ankylosis (disc fusion); Shox2 is required for cell proliferation and expression of osteogenic genes in the TMJ. Conditional knockout (Wnt1-Cre), histology, in situ hybridization, cell proliferation assays Mechanisms of development Medium 18514492
2010 Shox2 is required for normal skeletal, neural, and muscular development of the proximal forelimb; Shox2 deficiency causes axonal migration defects resulting in absence of radial and axillary nerves and abnormal triceps muscle development, identifying Shox2-dependent gene targets across multiple tissue types. Affymetrix microarray, in situ hybridization, nerve and muscle phenotype analysis in Shox2 knockout mice Developmental biology Medium 21156168
2011 Shox2 is required for specification of TrkB+/Ret+ and TrkB+/Ret- touch-sensitive mechanoreceptive neurons (category I low-threshold mechanoreceptors); Runx3 suppresses Shox2 while Shox2 is necessary for TrkB expression; conditional deletion of Shox2 dramatically impairs light touch responses. Conditional knockout, genetic epistasis (Runx3-/-;Bax-/- mutants), behavioral light touch assay The European journal of neuroscience High 22103411
2013 Shox2 controls the pacemaker gene program in embryoid bodies; loss of Shox2 slows spontaneous contraction and alters expression of HCN4, Cx45, Tbx2, Tbx3, BMP4 (down) and Cx40, Cx43, Nkx2.5, Tbx5 (up); adding BMP4 to Shox2 knockout EBs rescues the phenotype, establishing BMP4 as a downstream effector of Shox2 pacemaker signaling. Embryoid body differentiation, electrophysiology, gene expression analysis, BMP4 rescue, Noggin inhibition Stem cells and development High 23767866
2013 The Shox2-Cre knock-in allele recapitulates endogenous Shox2 expression (SAN, anterior palate, proximal limb bud); conditional deletion of Shox2 using Shox2-Cre yields SAN phenotypes resembling conventional Shox2 knockout. Knock-in mouse generation (LacZ and Cre), beta-galactosidase reporter, conditional knockout Genesis (New York, N.Y. : 2000) Medium 23620086
2014 SHOX2 directly activates NPPB transcription and activates ACAN via cooperation with the SOX trio (SOX5, SOX6, SOX9); SHOX2 interacts with SOX5/SOX6 by direct protein-protein interaction; SHOX2 dimerizes via specific protein domains identified by yeast two-hybrid and co-immunoprecipitation. Luciferase reporter assay, yeast two-hybrid, co-immunoprecipitation, immunohistochemistry PloS one Medium 24421874
2014 Tbx4 is a transcriptional activator of Shox2 in fore- and hindlimb development; Shox2 inhibits Tbx4 in forelimbs; Tbx4/TBX4 binds T-box binding sites within the mouse and human Shox2/SHOX2 promoter as shown by EMSA. Expression profiling, in situ hybridization, EMSA, genetic interaction analysis in Shox2-/- mice Developmental dynamics Medium 24347445
2014 SHOX2 is a direct target of miR-375 in breast cancer; SHOX2 acts as a transcription factor to upregulate TGF-β receptor I (TβR-I) expression, inducing EMT; TβR-I inhibition abolishes SHOX2-induced EMT, establishing SHOX2-TβR-I-TGFβ signaling as the mechanism of SHOX2-driven EMT. miRNA overexpression/rescue, luciferase reporter assay, TβR-I inhibitor experiments, invasion assays, in vivo dissemination assay Neoplasia (New York, N.Y.) Medium 24746361
2014 Mice lacking Shox2 in the brain display impaired cerebellar development: loss of Shox2 in Purkinje cells reduces Shh expression, causing precocious differentiation and migration of granule cell precursors and premature Bmp4 expression in the dorsal cerebellum; Shox2 mutant mice show impaired motor coordination. Cre-conditional knockout (Nestin-Cre), in situ hybridization, immunohistochemistry, behavioral motor assays Developmental biology Medium 25528224
2014 Genetic interaction between Shox2 and Hox genes (HoxA/D clusters) modulates proximal limb length; both Shox2 and Hox gene loss reduce Runx2 expression in the humerus, suggesting concerted regulation of cartilage maturation; Hox gene function influences Shox2 expression to a limited degree. Double mutant dosage experiments, fluorescence in situ hybridization (FISH), limb morphometry, Runx2 expression analysis Genetics Medium 25217052
2016 Shox2 controls stylopod patterning specifically through the osteogenic cell lineage, not other lineages; ChIP-Seq shows Shox2 robustly interacts with cis-regulatory enhancers around skeletogenic genes also bound by Hox-TALE factors; Shox2 acts as a repressor via interaction with proximal limb mesenchyme enhancers and antagonizes TALE factor repression in osteogenesis; genome-wide co-occupancy of Pbx, Meis, and Shox2 identified. Osteogenic lineage-specific conditional knockout, ChIP-Seq (Shox2, Pbx), RNA-Seq, transgenic enhancer assays Development (Cambridge, England) High 27287812
2016 Human SHOX2 p.H283Q missense mutation severely affects SHOX2 pacemaker function in transactivation studies and zebrafish rescue; a 3'UTR variant (c.*28T>C) creates a functional binding site for hsa-miR-92b-5p, reducing SHOX2 expression and associating with prolonged PR intervals and atrial fibrillation. Transactivation assays, zebrafish phenotypic rescue, miRNA binding site validation, patient plasma miRNA measurement Basic research in cardiology Medium 27138930
2018 A SHOX2 nonsense mutation (p.R194X) causes loss of transcriptional activity and co-segregates with familial atrial fibrillation, establishing SHOX2 loss-of-function as a mechanism for AF susceptibility. Sequencing, dual-luciferase reporter assay International journal of medical sciences Medium 30443179
2019 Shox2 controls osteogenesis of the anterior palatine process by binding distal cis-regulatory elements in an anterior palate-specific manner; ATAC-Seq and RNA-Seq show Shox2 regulates accessible chromatin and expression of pattern specification and skeletogenic genes; H3K27ac ChIP-Seq and transgenic enhancer assays confirm Shox2 binding to active anterior palate enhancers. Conditional KO, RNA-Seq, ATAC-Seq, H3K27ac ChIP-Seq, transgenic enhancer assays The Journal of biological chemistry High 31649032
2019 SHOX2 missense variants (p.G77D, p.P33R) impair transactivation activity in vitro; p.G77D causes dominant-negative reduction of heart rate and pericardial edema in zebrafish; p.P33R reduces Bmp4 target gene expression in zebrafish hearts, linking SHOX2 variants to sinus node dysfunction and AF through impaired transcriptional and BMP4 pathway activity. In vitro reporter assay, zebrafish overexpression/functional assay, in situ hybridization Frontiers in genetics Medium 31354791
2023 SHOX2 activates transcription of NPHP4, which in turn interferes with the Hippo-YAP signaling pathway, promoting prostate cancer cell proliferation and invasion. RNAi knockdown, SHOX2 overexpression, proliferation and invasion assays, pathway analysis iScience Low 37664594
2015 Shox2 is required for development of the facial motor nucleus; loss of Shox2 causes elevated cell death, impaired axonal projections of visceral motor neurons, altered Isl1 and Phox2b spatial expression, and loss of dorsomedial and ventromedial facial motor subnuclei. Nestin-Cre conditional knockout, immunohistochemistry, in situ hybridization BMC neuroscience Medium 26156498
2016 Shox2 overexpression in mesenchymal stem cells induces a pacemaker-like phenotype: upregulation of Tbx3, HCN4, and Cx45; downregulation of Nkx2.5 and Cx43; Shox2-transfected MSCs pace co-cultured cardiomyocytes at a faster rate. Lentiviral transfection, co-culture model, RT-qPCR, western blot, electrophysiology Molecular medicine reports Low 27222368
2021 After spinal cord injury (SCI), intrinsic excitability of Shox2 interneurons is maintained, but sensory afferent input shifts from mixed excitatory/inhibitory to predominantly excitatory, and serotonin (5-HT) modulation changes so that 5-HT predominantly depolarizes Shox2 INs via 5-HT7 and (post-SCI) 5-HT2B/2C receptors. Whole-cell patch-clamp recordings, pharmacological receptor characterization, complete thoracic transection model in mice The Journal of neuroscience Medium 34006587

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 BoxCar acquisition method enables single-shot proteomics at a depth of 10,000 proteins in 100 minutes. Nature methods 282 29735998
2007 Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation 197 17372176
2013 Locomotor rhythm generation linked to the output of spinal shox2 excitatory interneurons. Neuron 172 24267650
2016 Validation of the SHOX2/PTGER4 DNA Methylation Marker Panel for Plasma-Based Discrimination between Patients with Malignant and Nonmalignant Lung Disease. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 138 27544059
2022 5S Study: Safe and Simple Single Shot Pulmonary Vein Isolation With Pulsed Field Ablation Using Sedation. Circulation. Arrhythmia and electrophysiology 132 35617232
2017 Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot. Molecules and cells 111 28927262
2011 Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspirates. International journal of oncology 105 22108652
1998 SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development. Proceedings of the National Academy of Sciences of the United States of America 98 9482898
2022 Single-Shot 10K Proteome Approach: Over 10,000 Protein Identifications by Data-Independent Acquisition-Based Single-Shot Proteomics with Ion Mobility Spectrometry. Journal of proteome research 90 35522919
2021 Highly efficient multiplex editing: one-shot generation of 8× Nicotiana benthamiana and 12× Arabidopsis mutants. The Plant journal : for cell and molecular biology 85 33577114
2017 DNA Methylation Analysis of the SHOX2 and RASSF1A Panel in Bronchoalveolar Lavage Fluid for Lung Cancer Diagnosis. Journal of Cancer 82 29151944
2015 A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaker cell fate in the pulmonary vein myocardium and sinoatrial node. Development (Cambridge, England) 82 26138475
2019 A Third Shot at EGFR: New Opportunities in Cancer Therapy. Trends in pharmacological sciences 79 31706618
2018 Rifaximin in nonalcoholic fatty liver disease: hit multiple targets with a single shot. European journal of gastroenterology & hepatology 76 30096092
2007 Shox2 is required for chondrocyte proliferation and maturation in proximal limb skeleton. Developmental biology 74 17481601
2025 One-shot design of functional protein binders with BindCraft. Nature 73 40866699
2014 SHOX2 is a direct miR-375 target and a novel epithelial-to-mesenchymal transition inducer in breast cancer cells. Neoplasia (New York, N.Y.) 71 24746361
2013 Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia. Basic research in cardiology 66 23455426
2016 Shot and Patronin polarise microtubules to direct membrane traffic and biogenesis of microvilli in epithelia. Journal of cell science 63 27231092
2008 Shox2-deficiency leads to dysplasia and ankylosis of the temporomandibular joint in mice. Mechanisms of development 59 18514492
2011 Shot-gun proteomic analysis of mitochondrial D-loop DNA binding proteins: identification of mitochondrial histones. Molecular bioSystems 55 21359316
2013 Assessment of SHOX2 methylation in EBUS-TBNA specimen improves accuracy in lung cancer staging. Annals of oncology : official journal of the European Society for Medical Oncology 53 24026539
2022 Neural representational geometry underlies few-shot concept learning. Proceedings of the National Academy of Sciences of the United States of America 52 36251997
2016 Simple and Reproducible Sample Preparation for Single-Shot Phosphoproteomics with High Sensitivity. Methods in molecular biology (Clifton, N.J.) 46 26584931
2022 DeepGOZero: improving protein function prediction from sequence and zero-shot learning based on ontology axioms. Bioinformatics (Oxford, England) 44 35758802
2016 Coding and non-coding variants in the SHOX2 gene in patients with early-onset atrial fibrillation. Basic research in cardiology 43 27138930
2011 Functional redundancy between human SHOX and mouse Shox2 genes in the regulation of sinoatrial node formation and pacemaking function. The Journal of biological chemistry 42 21454626
2012 Hoxa11 and Hoxd11 regulate chondrocyte differentiation upstream of Runx2 and Shox2 in mice. PloS one 41 22916278
2025 BindCraft: one-shot design of functional protein binders. bioRxiv : the preprint server for biology 38 39677777
2014 Analysis of SHOX2 methylation as an aid to cytology in lung cancer diagnosis. Cancer genomics & proteomics 38 25331797
2013 Generation of Shox2-Cre allele for tissue specific manipulation of genes in the developing heart, palate, and limb. Genesis (New York, N.Y. : 2000) 38 23620086
2010 Shox2 function couples neural, muscular and skeletal development in the proximal forelimb. Developmental biology 38 21156168
2025 Zero-shot evaluation reveals limitations of single-cell foundation models. Genome biology 37 40251685
2020 Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer. Journal of cancer research and clinical oncology 36 32266538
2023 ZeroBind: a protein-specific zero-shot predictor with subgraph matching for drug-target interactions. Nature communications 35 38030641
2016 Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract. Clinical epigenetics 35 27999621
2017 Kinobead and Single-Shot LC-MS Profiling Identifies Selective PKD Inhibitors. Journal of proteome research 34 28102076
2023 Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets. International journal of molecular sciences 31 37373310
2012 The role of Shox2 in SAN development and function. Pediatric cardiology 31 22307400
2011 Dependence on the transcription factor Shox2 for specification of sensory neurons conveying discriminative touch. The European journal of neuroscience 31 22103411
2002 The ecological and physiological costs of lead shot and immunological challenge to developing western bluebirds. Ecotoxicology (London, England) 31 12092753
2024 Zero-shot prediction of mutation effects with multimodal deep representation learning guides protein engineering. Cell research 30 38969803
2021 Multi-Omic Single-Shot Technology for Integrated Proteome and Lipidome Analysis. Analytical chemistry 30 33617230
2017 MiR-375 suppresses invasion and metastasis by direct targeting of SHOX2 in esophageal squamous cell carcinoma. Acta biochimica et biophysica Sinica 30 28069583
2022 The Diagnostic Potential of SHOX2 and RASSF1A DNA Methylation in Early Lung Adenocarcinoma. Frontiers in oncology 29 35837113
2018 A SHOX2 loss-of-function mutation underlying familial atrial fibrillation. International journal of medical sciences 29 30443179
2002 The ultimate chip shot: can microarray technology deliver for neuroscience? Genes, brain, and behavior 29 12886947
2020 DeepKinZero: zero-shot learning for predicting kinase-phosphosite associations involving understudied kinases. Bioinformatics (Oxford, England) 28 32044914
2024 Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins. Nature communications 27 38418820
2020 The TCR Repertoire Reconstitution in Multiple Sclerosis: Comparing One-Shot and Continuous Immunosuppressive Therapies. Frontiers in immunology 27 32328061
2023 DNA Nanoclusters Combined with One-Shot Radiotherapy Augment Cancer Immunotherapy Efficiency. Advanced materials (Deerfield Beach, Fla.) 26 36745572
2020 Performance Evaluation of SHOX2 and RASSF1A Methylation for the Aid in Diagnosis of Lung Cancer Based on the Analysis of FFPE Specimen. Frontiers in oncology 26 33425721
2013 Elevated SHOX2 expression is associated with tumor recurrence of hepatocellular carcinoma. Annals of surgical oncology 26 23851611
2013 3'UTRs take a long shot in the brain. BioEssays : news and reviews in molecular, cellular and developmental biology 26 24115048
2019 Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation. Frontiers in genetics 24 31354791
2015 Diagnostic value of SHOX2 DNA methylation in lung cancer: a meta-analysis. OncoTargets and therapy 24 26640383
2010 A versatile diffractive maskless lithography for single-shot and serial microfabrication. Optics express 24 20589036
2022 Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity. Acta pharmaceutica Sinica. B 23 35846427
2022 A fast blind zero-shot denoiser. Nature machine intelligence 23 36415333
2021 Spinal Cord Injury Alters Spinal Shox2 Interneurons by Enhancing Excitatory Synaptic Input and Serotonergic Modulation While Maintaining Intrinsic Properties in Mouse. The Journal of neuroscience : the official journal of the Society for Neuroscience 23 34006587
2019 Shox2 regulates osteogenic differentiation and pattern formation during hard palate development in mice. The Journal of biological chemistry 23 31649032
2015 Diagnosis of Lung Cancer by SHOX2 Gene Methylation Assay. Molecular diagnosis & therapy 23 26014676
2014 Genetic interactions between Shox2 and Hox genes during the regional growth and development of the mouse limb. Genetics 23 25217052
2024 Metasurface array for single-shot spectroscopic ellipsometry. Light, science & applications 21 38600108
2023 Rapid protection induced by a single-shot Lassa vaccine in male cynomolgus monkeys. Nature communications 20 36906645
2023 FLInt: single shot safe harbor transgene integration via Fluorescent Landmark Interference. G3 (Bethesda, Md.) 19 36805659
2019 MiR-223-3p inhibits proliferation and metastasis of oral squamous cell carcinoma by targeting SHOX2. European review for medical and pharmacological sciences 19 31486492
2014 Yeast systems biology: our best shot at modeling a cell. Genetics 19 25316779
2013 Comparative transgenic analysis of enhancers from the human SHOX and mouse Shox2 genomic regions. Human molecular genetics 19 23575226
2019 One-shot optimization of multiple enzyme parameters: Tailoring glucose oxidase for pH and electron mediators. Biotechnology and bioengineering 18 31520472
2014 NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development. PloS one 18 24421874
2014 Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination. Developmental biology 18 25528224
2013 Shox2 regulates the pacemaker gene program in embryoid bodies. Stem cells and development 18 23767866
2024 Evaluating the comprehensive diagnosis efficiency of lung cancer, including measurement of SHOX2 and RASSF1A gene methylation. BMC cancer 17 38429660
2023 A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment? Journal of thrombosis and haemostasis : JTH 17 37225021
2023 Single-Shot Solid-Phase Synthesis of Full-Length H2 Relaxin Disulfide Surrogates. Angewandte Chemie (International ed. in English) 16 36515186
2020 A Novel Diagnosis Method Based on Methylation Analysis of SHOX2 and Serum Biomarker for Early Stage Lung Cancer. Cancer control : journal of the Moffitt Cancer Center 16 33167712
2016 A unique stylopod patterning mechanism by Shox2-controlled osteogenesis. Development (Cambridge, England) 16 27287812
2021 Mitochondrial cytochrome c shot towards histone chaperone condensates in the nucleus. FEBS open bio 15 33938164
2020 Three-dimensional single-shot ptychography. Optics express 15 32672178
2014 Tbx4 interacts with the short stature homeobox gene Shox2 in limb development. Developmental dynamics : an official publication of the American Association of Anatomists 15 24347445
2018 Shox2: The Role in Differentiation and Development of Cardiac Conduction System. The Tohoku journal of experimental medicine 14 29503396
2014 Phosphorylation of Shox2 is required for its function to control sinoatrial node formation. Journal of the American Heart Association 14 24847033
2023 A single-shot prophylactic tumor vaccine enabled by an injectable biomembrane hydrogel. Acta biomaterialia 13 37574158
2023 SHOX2 promotes prostate cancer proliferation and metastasis through disruption of the Hippo-YAP pathway. iScience 13 37664594
2020 The performance of the SHOX2/PTGER4 methylation assay is influenced by cancer stage, age, type and differentiation. Biomarkers in medicine 13 32250153
2023 CREaTor: zero-shot cis-regulatory pattern modeling with attention mechanisms. Genome biology 12 37996959
2017 Spin Pumping and Shot Noise in Ferrimagnets: Bridging Ferro- and Antiferromagnets. Physical review letters 12 29219498
2015 Shox2 is required for the proper development of the facial motor nucleus and the establishment of the facial nerves. BMC neuroscience 12 26156498
2021 SCIRT lncRNA Blocks the Shot of Breast Cancer Cells Self-Renewal Mechanism. Cancer research 11 33526468
2021 One-shot dual gene editing for drug-resistant pancreatic cancer therapy. Biomaterials 11 34781244
2016 Integration of an Optical Ring Resonator Biosensor into a Self-Contained Microfluidic Cartridge with Active, Single-Shot Micropumps. Micromachines 11 30404337
2014 Overexpression of Shox2 leads to congenital dysplasia of the temporomandibular joint in mice. International journal of molecular sciences 10 25062348
2023 Multilingual translation for zero-shot biomedical classification using BioTranslator. Nature communications 9 36759510
2023 Diagnostic performance of RASSF1A and SHOX2 methylation combined with EGFR mutations for differentiation between small pulmonary nodules. Journal of cancer research and clinical oncology 9 37097393
2023 Combined Methylation of SHOX2 and RASSF1A Genes in Diagnosing Malignant Pleural Effusion. Discovery medicine 9 37811622
2019 Experiences of sexual and gender minorities in an urban enclave of Haiti: despised, beaten, stoned, stabbed, shot and raped. Culture, health & sexuality 9 31318325
2017 Role of SHOX2 in the development of intervertebral disc degeneration. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 9 26697824
2016 Shox2 influences mesenchymal stem cell fate in a co-culture model in vitro. Molecular medicine reports 9 27222368
2017 Comparative expression analysis of Shox2-deficient embryonic stem cell-derived sinoatrial node-like cells. Stem cell research 8 28390247