{"gene":"GSC","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1996,"finding":"GSC (goosecoid) homeoproteins share a conserved engrailed homology (eh1) repression domain present in all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, which mediates active transcriptional repression in vivo; this domain is required for active repression activity in vivo (distinct from cell-culture-identified repression domains).","method":"In vivo repression assay using homeodomain swap (retargeting engrailed repression domain via ftz), transgenic rescue experiments, functional mapping of conserved domains","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo functional assay with domain swaps, mutagenesis, and rescue transgenes in a single rigorous study; conserved domain identified across multiple homeoprotein classes","pmids":["8898227"],"is_preprint":false},{"year":1995,"finding":"Goosecoid (gsc) is required for dorsal patterning of the Xenopus mesoderm: antisense gsc RNA injection causes ventralization of embryos, and gsc is required for LiCl-induced dorsalization, establishing gsc as a necessary component of the dorsal patterning pathway during gastrulation.","method":"Loss-of-function via antisense RNA injection in Xenopus embryos; marker gene expression analysis; LiCl and UV-irradiation epistasis experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — antisense loss-of-function with multiple marker genes and epistasis experiments, replicated across gain- and loss-of-function approaches in a single study","pmids":["7489713"],"is_preprint":false},{"year":1994,"finding":"The human GSC gene encodes a homeodomain protein with 100% conserved homeodomain sequence across vertebrates; the gene consists of three exons with conserved exon-intron boundaries and maps to human chromosome 14q32.1.","method":"Genomic library cloning, DNA sequencing, somatic cell hybrid mapping, chromosomal in situ hybridization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and chromosomal mapping with two orthogonal methods; single lab but definitive localization result","pmids":["7916327"],"is_preprint":false},{"year":2007,"finding":"Foxh1 recruits Goosecoid (Gsc) to form a DNA-binding complex that negatively regulates Mixl1 gene expression during mouse gastrulation; Gsc in turn recruits histone deacetylases (HDACs) to repress Mixl1 transcription, and ectopic Gsc repression of Mixl1 is Foxh1-dependent.","method":"Co-immunoprecipitation (Foxh1-Gsc complex), ectopic expression in embryoid bodies, Foxh1-null embryo analysis, HDAC recruitment assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing Foxh1-Gsc complex, in vivo knockout phenotype, HDAC recruitment, and ectopic expression rescue with Foxh1-dependency; multiple orthogonal methods","pmids":["17568773"],"is_preprint":false},{"year":2006,"finding":"Gsc genetically interacts with Dkk1 in anterior head morphogenesis in mouse; loss of Gsc alters expression of Dkk1, WNT genes, and a WNT signaling reporter, indicating Gsc functions as a negative regulator of Wnt signaling in the anterior mesendoderm.","method":"Genetic epistasis using Gsc/Dkk1 double-mutant mice, reporter gene analysis for Wnt signaling, in situ hybridization for Dkk1 and Wnt gene expression","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double mutants and reporter analysis in a single lab study; establishes pathway position of Gsc upstream of Wnt signaling","pmids":["17127040"],"is_preprint":false},{"year":2012,"finding":"Multiple transcription factors (Lim1/Lhx1, Otx2, Mix1, Siamois, VegT) bind in a stepwise manner to cis-regulatory modules (CRMs) of the gsc promoter in Xenopus: Siamois and VegT bind first at blastula stage, and all five factors bind at gastrula stage; Lim1 and Otx2 binding persists at neurula stage, corresponding to their co-expression in the prechordal plate.","method":"Reporter analysis using sperm nuclear transplantation and DNA injection; ChIP-qPCR for five transcription factors at gsc CRMs across developmental stages; expression pattern analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-qPCR with multiple transcription factors across multiple developmental stages combined with functional reporter assays; multiple orthogonal methods in a rigorous single study","pmids":["22492356"],"is_preprint":false},{"year":2016,"finding":"GSC (goosecoid) is required for definitive endoderm differentiation of human embryonic stem cells; GSC expression is regulated in trans by the lncRNA DIGIT, and restoration of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient cells.","method":"DIGIT deletion and depletion experiments; GSC rescue by endogenous activation; SMAD3 ChIP-seq; hESC differentiation assays; mouse ortholog functional analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (endoderm differentiation), rescue experiment, ChIP-seq; single lab with multiple orthogonal methods","pmids":["27705785"],"is_preprint":false},{"year":2024,"finding":"Gsc directly binds the proximal promoter region of the BMP4 target gene ventx3.2 at a defined Gsc response element (GRE) in Xenopus gastrulae and acts as a transcriptional repressor; point mutation within the GRE completely abolishes Gsc repressive activity on ventx3.2.","method":"Genome-wide Gsc ChIP-seq; serial deletion and site-directed mutagenesis of ventx3.2 promoter; ChIP-PCR confirming direct binding to GRE; marginal zone functional assays","journal":"Molecules and cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP-seq plus mutagenesis plus ChIP-PCR confirming direct binding in a single study; multiple orthogonal methods with site-directed mutagenesis abolishing activity","pmids":["38522664"],"is_preprint":false},{"year":2016,"finding":"GSC (goosecoid) participates in a TBP family-insensitive (TFI) transcription network with T-box genes, Otx2, and other organizer genes in Xenopus; recruitment of Gcn5 (Kat2a) co-activator to TFI gene promoters including gsc is increased upon depletion of TBP family factors, suggesting a non-canonical transcription initiation mechanism for gsc.","method":"TBP family triple-knockdown, α-amanitin treatment, transcriptome profiling, ChIP for RNA Pol II and Gcn5 at gsc promoter","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with transcriptome profiling and ChIP analysis; single lab with multiple orthogonal methods but indirect evidence for Gsc-specific mechanism","pmids":["26952988"],"is_preprint":false},{"year":1997,"finding":"Cortical rotation (beta-catenin nuclear translocation) in Xenopus is necessary but not sufficient for gsc expression; overexpression of beta-catenin in animal cap explants activates siamois (sia) and nr3 but not gsc, indicating gsc requires additional mesodermal induction signals beyond Wnt/beta-catenin for activation and maintenance.","method":"Beta-catenin overexpression in animal cap explants, UV-irradiation to block cortical rotation, in situ hybridization for gsc/sia/nr3 markers across developmental stages","journal":"The International journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment with gain-of-function and loss-of-function conditions using spatial marker analysis; single lab, two orthogonal approaches","pmids":["9415495"],"is_preprint":false},{"year":2010,"finding":"In zebrafish, maternally deposited Lnx-2b restricts gsc expression to the dorsal mesoderm by limiting both Nodal signaling and Bozozok (Boz) activity; overexpression of Boz together with Lnx-2b depletion causes robust ectopic gsc expression in all blastomeres, demonstrating that Nodal signals are required for gsc expression even when Boz is elevated.","method":"Boz overexpression, Lnx-2b morpholino depletion, targeted single-cell injection at 128-cell stage, epistasis analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with double manipulation (overexpression + depletion), targeted cell injection; single lab but multiple orthogonal approaches","pmids":["20971071"],"is_preprint":false},{"year":2000,"finding":"In porcine embryos, gsc expression localizes to one side of the embryoblast at day 10 and anterior to the primitive streak at day 13, consistent with its role as an early marker of the organizer/anterior mesendoderm in vertebrates.","method":"RT-PCR cloning of porcine gsc homeodomain region, in situ hybridization on whole-mount porcine embryos, relative expression quantification across days 9-13 of pregnancy","journal":"Molecular reproduction and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, descriptive localization in a new species without functional consequence established; confirms conservation of expression pattern","pmids":["10602267"],"is_preprint":false},{"year":2013,"finding":"Ethanol-induced upregulation of GSC expression in human embryonic carcinoma cell-derived embryoid bodies is mediated by Nodal signaling, placing GSC downstream of Nodal in the context of ethanol teratogenicity during early embryonic differentiation.","method":"Chronic ethanol treatment of embryoid bodies, gene expression profiling, pathway analysis, Nodal signaling inhibitor experiments","journal":"Journal of applied toxicology : JAT","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway assignment based on pharmacological inhibition without direct mechanistic dissection of Nodal-GSC regulatory link","pmids":["23378141"],"is_preprint":false}],"current_model":"GSC (goosecoid) is a homeodomain transcription factor that functions primarily as an active transcriptional repressor through a conserved eh1 domain shared with engrailed-class homeoproteins; it directly binds target gene promoters (e.g., ventx3.2) at defined Gsc response elements and recruits histone deacetylases via Foxh1 to repress target genes (e.g., Mixl1); its expression is activated downstream of integrated Nodal, Wnt, and maternal VegT/Siamois signals through cis-regulatory modules, and it functions as a necessary component of dorsal patterning in vertebrate gastrulation and definitive endoderm formation, with genetic interactions placing it upstream of Wnt/Dkk1 signaling in anterior head development."},"narrative":{"mechanistic_narrative":"GSC (goosecoid) is a homeodomain transcription factor that acts as an active transcriptional repressor and serves as a necessary component of dorsal mesoderm patterning during vertebrate gastrulation and of definitive endoderm formation [PMID:7489713, PMID:27705785]. Its repressive activity depends on a conserved engrailed-homology (eh1) domain shared across en-, gsc-, Nk- and msh-class homeoproteins, which mediates active repression in vivo [PMID:8898227]. Gsc binds defined response elements in target gene promoters and represses transcription directly: it occupies a Gsc response element in the BMP4 target ventx3.2, where point mutation of the element abolishes its repressive activity [PMID:38522664], and it is recruited by Foxh1 into a DNA-binding complex that silences Mixl1 by engaging histone deacetylases [PMID:17568773]. Loss of Gsc ventralizes Xenopus embryos and blocks LiCl-induced dorsalization [PMID:7489713], and Gsc genetically interacts with Dkk1 to negatively regulate Wnt signaling during anterior head morphogenesis [PMID:17127040]. gsc transcription itself is the integration point of multiple inductive inputs: stepwise binding of Siamois, VegT, Lim1/Lhx1, Otx2 and Mix1 at its cis-regulatory modules drives stage-specific expression [PMID:22492356], with Wnt/β-catenin necessary but not sufficient and Nodal signaling additionally required for activation [PMID:9415495, PMID:20971071]. In human embryonic stem cells, GSC is required for definitive endoderm differentiation and is regulated in trans by the lncRNA DIGIT [PMID:27705785].","teleology":[{"year":1994,"claim":"Establishing the human GSC gene structure and its highly conserved homeodomain anchored goosecoid as a bona fide vertebrate homeobox transcription factor and provided a genomic locus for study.","evidence":"Genomic cloning, sequencing, and chromosomal mapping to 14q32.1","pmids":["7916327"],"confidence":"Medium","gaps":["No functional or DNA-binding activity demonstrated in this study","Target genes unknown"]},{"year":1995,"claim":"Antisense loss-of-function showed that gsc is genuinely required for dorsal mesoderm patterning rather than merely correlated with it, placing it within the dorsalization pathway.","evidence":"Antisense RNA injection in Xenopus with marker analysis and LiCl/UV epistasis","pmids":["7489713"],"confidence":"High","gaps":["Direct transcriptional targets not identified","Molecular mechanism of repression not addressed"]},{"year":1996,"claim":"Identification of the conserved eh1 repression domain explained how goosecoid-class homeoproteins act as active repressors in vivo, distinguishing this from cell-culture repression activities.","evidence":"In vivo homeodomain-swap retargeting, mutagenesis, and rescue transgenes","pmids":["8898227"],"confidence":"High","gaps":["Corepressors engaged by eh1 not defined in this study","Direct in vivo targets not mapped"]},{"year":1997,"claim":"Epistasis revealed that Wnt/β-catenin alone cannot activate gsc, demonstrating it requires additional mesoderm-inducing signals and refining where gsc sits in the signaling hierarchy.","evidence":"β-catenin overexpression in animal caps and UV cortical-rotation block in Xenopus","pmids":["9415495"],"confidence":"Medium","gaps":["Identity of the additional inducing signal not pinned in this study","Direct cis-elements not defined"]},{"year":2006,"claim":"Double-mutant genetics placed Gsc upstream of Dkk1/Wnt, framing it as a negative regulator of Wnt signaling in anterior head development.","evidence":"Gsc/Dkk1 double-mutant mice with Wnt reporter and in situ analysis","pmids":["17127040"],"confidence":"Medium","gaps":["Whether Gsc regulates Dkk1 directly not established","No direct promoter binding shown"]},{"year":2007,"claim":"Defining the Foxh1-Gsc complex and HDAC recruitment provided a concrete molecular mechanism for Gsc repression of a specific target (Mixl1) and explained how Gsc reaches its DNA targets.","evidence":"Reciprocal Co-IP, Foxh1-null embryos, embryoid-body ectopic expression, HDAC recruitment assay in mouse","pmids":["17568773"],"confidence":"High","gaps":["Specific HDAC isoform not identified","Generalizability beyond Mixl1 not tested here"]},{"year":2010,"claim":"Zebrafish epistasis showed Nodal signaling is required for gsc expression even when Bozozok is elevated, clarifying the combinatorial maternal/zygotic inputs that spatially restrict gsc.","evidence":"Boz overexpression with Lnx-2b morpholino depletion and targeted single-cell injection","pmids":["20971071"],"confidence":"Medium","gaps":["Direct cis-regulatory targets of Nodal/Boz on gsc not mapped","Cross-species applicability not tested"]},{"year":2012,"claim":"Stepwise occupancy of gsc CRMs by five transcription factors resolved how distinct inductive signals are integrated temporally to drive stage-specific gsc transcription.","evidence":"ChIP-qPCR for Siamois, VegT, Lim1, Otx2, Mix1 across developmental stages plus reporter assays in Xenopus","pmids":["22492356"],"confidence":"High","gaps":["Functional necessity of each binding event not individually dissected","Cofactors at CRMs not identified"]},{"year":2016,"claim":"Demonstrating that GSC is required for definitive endoderm differentiation of human ESCs and is controlled by the lncRNA DIGIT extended Gsc function to human endoderm specification and added a trans-regulatory layer.","evidence":"DIGIT deletion/depletion, GSC endogenous rescue, SMAD3 ChIP-seq, hESC differentiation assays","pmids":["27705785"],"confidence":"Medium","gaps":["Mechanism by which DIGIT regulates GSC not fully resolved","Direct GSC endoderm targets in human cells not mapped"]},{"year":2016,"claim":"Inclusion of gsc in a TBP-family-insensitive transcription network with Gcn5 recruitment raised the possibility of non-canonical transcription initiation at the gsc locus.","evidence":"TBP-family triple-knockdown, α-amanitin, transcriptome profiling, RNA Pol II/Gcn5 ChIP in Xenopus","pmids":["26952988"],"confidence":"Medium","gaps":["Evidence for gsc-specific mechanism is indirect","Functional consequence of Gcn5 recruitment not established"]},{"year":2024,"claim":"Genome-wide ChIP-seq with promoter mutagenesis demonstrated that Gsc directly binds a defined response element in the ventx3.2 promoter to repress this BMP4 target, providing direct in vivo evidence of sequence-specific Gsc repression.","evidence":"Gsc ChIP-seq, serial deletion/site-directed mutagenesis of ventx3.2 promoter, ChIP-PCR, marginal zone assays in Xenopus","pmids":["38522664"],"confidence":"High","gaps":["Cofactors at the GRE not identified","Full genome-wide target set not functionally validated"]},{"year":null,"claim":"How Gsc's eh1 domain, Foxh1 partnership, and direct GRE binding are integrated into a unified repression mechanism across its full target repertoire, and whether human disease links exist, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No comprehensive genome-wide functional target map","Corepressor complexes incompletely defined","No Mendelian disease association established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9,10]}],"complexes":[],"partners":["FOXH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56915","full_name":"Homeobox protein goosecoid","aliases":[],"length_aa":257,"mass_kda":28.1,"function":"Regulates chordin (CHRD). May play a role in spatial programing within discrete embryonic fields or lineage compartments during organogenesis. In concert with NKX3-2, plays a role in defining the structural components of the middle ear; required for the development of the entire tympanic ring (By similarity). Probably involved in the regulatory networks that define neural crest cell fate specification and determine mesoderm cell lineages in mammals","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P56915/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GSC","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GSC","total_profiled":1310},"omim":[{"mim_id":"621547","title":"ZDHHC PALMITOYLTRANSFERASE 4; ZDHHC4","url":"https://www.omim.org/entry/621547"},{"mim_id":"619391","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 157; CCDC157","url":"https://www.omim.org/entry/619391"},{"mim_id":"618199","title":"APOBEC1 COMPLEMENTATION FACTOR; A1CF","url":"https://www.omim.org/entry/618199"},{"mim_id":"610976","title":"APOLIPOPROTEIN B mRNA EDITING ENZYME, CATALYTIC POLYPEPTIDE-LIKE 3H; APOBEC3H","url":"https://www.omim.org/entry/610976"},{"mim_id":"608229","title":"NANOS C2HC-TYPE ZINC FINGER 3; NANOS3","url":"https://www.omim.org/entry/608229"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adipose tissue","ntpm":4.0},{"tissue":"breast","ntpm":7.1}],"url":"https://www.proteinatlas.org/search/GSC"},"hgnc":{"alias_symbol":["GSC1"],"prev_symbol":[]},"alphafold":{"accession":"P56915","domains":[{"cath_id":"1.10.10.60","chopping":"170-224","consensus_level":"high","plddt":94.1976,"start":170,"end":224}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56915","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56915-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56915-F1-predicted_aligned_error_v6.png","plddt_mean":63.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GSC","jax_strain_url":"https://www.jax.org/strain/search?query=GSC"},"sequence":{"accession":"P56915","fasta_url":"https://rest.uniprot.org/uniprotkb/P56915.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56915/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56915"}},"corpus_meta":[{"pmid":"8898227","id":"PMC_8898227","title":"A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo.","date":"1996","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8898227","citation_count":253,"is_preprint":false},{"pmid":"7489713","id":"PMC_7489713","title":"The role of gsc and BMP-4 in dorsal-ventral patterning of the marginal zone in Xenopus: a loss-of-function study using antisense RNA.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7489713","citation_count":125,"is_preprint":false},{"pmid":"9209021","id":"PMC_9209021","title":"Cloning of the Candida albicans homolog of Saccharomyces cerevisiae GSC1/FKS1 and its involvement in beta-1,3-glucan synthesis.","date":"1997","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9209021","citation_count":104,"is_preprint":false},{"pmid":"11013231","id":"PMC_11013231","title":"Cell wall assembly by Pneumocystis carinii. Evidence for a unique gsc-1 subunit mediating beta -1,3-glucan deposition.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11013231","citation_count":75,"is_preprint":false},{"pmid":"23175633","id":"PMC_23175633","title":"Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis.","date":"2012","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23175633","citation_count":69,"is_preprint":false},{"pmid":"34054725","id":"PMC_34054725","title":"Thyroseq v3, Afirma GSC, and microRNA Panels Versus Previous Molecular Tests in the Preoperative Diagnosis of Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.","date":"2021","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34054725","citation_count":61,"is_preprint":false},{"pmid":"31665322","id":"PMC_31665322","title":"Real-world Comparison of Afirma GEC and GSC for the Assessment of Cytologically Indeterminate Thyroid Nodules.","date":"2020","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31665322","citation_count":61,"is_preprint":false},{"pmid":"27705785","id":"PMC_27705785","title":"DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27705785","citation_count":59,"is_preprint":false},{"pmid":"30383497","id":"PMC_30383497","title":"STATISTICAL COMPARISON OF AFIRMA GSC AND AFIRMA GEC OUTCOMES IN A COMMUNITY ENDOCRINE SURGICAL PRACTICE: EARLY FINDINGS.","date":"2018","source":"Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists","url":"https://pubmed.ncbi.nlm.nih.gov/30383497","citation_count":55,"is_preprint":false},{"pmid":"32963699","id":"PMC_32963699","title":"Ginseng-Sanqi-Chuanxiong (GSC) Extracts Ameliorate Diabetes-Induced Endothelial Cell Senescence through Regulating Mitophagy via the AMPK Pathway.","date":"2020","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/32963699","citation_count":47,"is_preprint":false},{"pmid":"33789726","id":"PMC_33789726","title":"Glioblastoma stem cell (GSC)-derived PD-L1-containing exosomes activates AMPK/ULK1 pathway mediated autophagy to increase temozolomide-resistance in glioblastoma.","date":"2021","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/33789726","citation_count":45,"is_preprint":false},{"pmid":"25661868","id":"PMC_25661868","title":"Soma influences GSC progeny differentiation via the cell adhesion-mediated steroid-let-7-Wingless signaling cascade that regulates chromatin dynamics.","date":"2015","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/25661868","citation_count":41,"is_preprint":false},{"pmid":"20233776","id":"PMC_20233776","title":"Clinically significant micafungin resistance in Candida albicans involves modification of a glucan synthase catalytic subunit GSC1 (FKS1) allele followed by loss of heterozygosity.","date":"2010","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/20233776","citation_count":40,"is_preprint":false},{"pmid":"3001496","id":"PMC_3001496","title":"Forskolin potentiation of cholera toxin-stimulated cyclic AMP accumulation in intact C6-2B cells. 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domains).\",\n      \"method\": \"In vivo repression assay using homeodomain swap (retargeting engrailed repression domain via ftz), transgenic rescue experiments, functional mapping of conserved domains\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo functional assay with domain swaps, mutagenesis, and rescue transgenes in a single rigorous study; conserved domain identified across multiple homeoprotein classes\",\n      \"pmids\": [\"8898227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Goosecoid (gsc) is required for dorsal patterning of the Xenopus mesoderm: antisense gsc RNA injection causes ventralization of embryos, and gsc is required for LiCl-induced dorsalization, establishing gsc as a necessary component of the dorsal patterning pathway during gastrulation.\",\n      \"method\": \"Loss-of-function via antisense RNA injection in Xenopus embryos; marker gene expression analysis; LiCl and UV-irradiation epistasis experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antisense loss-of-function with multiple marker genes and epistasis experiments, replicated across gain- and loss-of-function approaches in a single study\",\n      \"pmids\": [\"7489713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human GSC gene encodes a homeodomain protein with 100% conserved homeodomain sequence across vertebrates; the gene consists of three exons with conserved exon-intron boundaries and maps to human chromosome 14q32.1.\",\n      \"method\": \"Genomic library cloning, DNA sequencing, somatic cell hybrid mapping, chromosomal in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and chromosomal mapping with two orthogonal methods; single lab but definitive localization result\",\n      \"pmids\": [\"7916327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Foxh1 recruits Goosecoid (Gsc) to form a DNA-binding complex that negatively regulates Mixl1 gene expression during mouse gastrulation; Gsc in turn recruits histone deacetylases (HDACs) to repress Mixl1 transcription, and ectopic Gsc repression of Mixl1 is Foxh1-dependent.\",\n      \"method\": \"Co-immunoprecipitation (Foxh1-Gsc complex), ectopic expression in embryoid bodies, Foxh1-null embryo analysis, HDAC recruitment assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing Foxh1-Gsc complex, in vivo knockout phenotype, HDAC recruitment, and ectopic expression rescue with Foxh1-dependency; multiple orthogonal methods\",\n      \"pmids\": [\"17568773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Gsc genetically interacts with Dkk1 in anterior head morphogenesis in mouse; loss of Gsc alters expression of Dkk1, WNT genes, and a WNT signaling reporter, indicating Gsc functions as a negative regulator of Wnt signaling in the anterior mesendoderm.\",\n      \"method\": \"Genetic epistasis using Gsc/Dkk1 double-mutant mice, reporter gene analysis for Wnt signaling, in situ hybridization for Dkk1 and Wnt gene expression\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double mutants and reporter analysis in a single lab study; establishes pathway position of Gsc upstream of Wnt signaling\",\n      \"pmids\": [\"17127040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Multiple transcription factors (Lim1/Lhx1, Otx2, Mix1, Siamois, VegT) bind in a stepwise manner to cis-regulatory modules (CRMs) of the gsc promoter in Xenopus: Siamois and VegT bind first at blastula stage, and all five factors bind at gastrula stage; Lim1 and Otx2 binding persists at neurula stage, corresponding to their co-expression in the prechordal plate.\",\n      \"method\": \"Reporter analysis using sperm nuclear transplantation and DNA injection; ChIP-qPCR for five transcription factors at gsc CRMs across developmental stages; expression pattern analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-qPCR with multiple transcription factors across multiple developmental stages combined with functional reporter assays; multiple orthogonal methods in a rigorous single study\",\n      \"pmids\": [\"22492356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSC (goosecoid) is required for definitive endoderm differentiation of human embryonic stem cells; GSC expression is regulated in trans by the lncRNA DIGIT, and restoration of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient cells.\",\n      \"method\": \"DIGIT deletion and depletion experiments; GSC rescue by endogenous activation; SMAD3 ChIP-seq; hESC differentiation assays; mouse ortholog functional analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (endoderm differentiation), rescue experiment, ChIP-seq; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27705785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Gsc directly binds the proximal promoter region of the BMP4 target gene ventx3.2 at a defined Gsc response element (GRE) in Xenopus gastrulae and acts as a transcriptional repressor; point mutation within the GRE completely abolishes Gsc repressive activity on ventx3.2.\",\n      \"method\": \"Genome-wide Gsc ChIP-seq; serial deletion and site-directed mutagenesis of ventx3.2 promoter; ChIP-PCR confirming direct binding to GRE; marginal zone functional assays\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP-seq plus mutagenesis plus ChIP-PCR confirming direct binding in a single study; multiple orthogonal methods with site-directed mutagenesis abolishing activity\",\n      \"pmids\": [\"38522664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSC (goosecoid) participates in a TBP family-insensitive (TFI) transcription network with T-box genes, Otx2, and other organizer genes in Xenopus; recruitment of Gcn5 (Kat2a) co-activator to TFI gene promoters including gsc is increased upon depletion of TBP family factors, suggesting a non-canonical transcription initiation mechanism for gsc.\",\n      \"method\": \"TBP family triple-knockdown, α-amanitin treatment, transcriptome profiling, ChIP for RNA Pol II and Gcn5 at gsc promoter\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with transcriptome profiling and ChIP analysis; single lab with multiple orthogonal methods but indirect evidence for Gsc-specific mechanism\",\n      \"pmids\": [\"26952988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cortical rotation (beta-catenin nuclear translocation) in Xenopus is necessary but not sufficient for gsc expression; overexpression of beta-catenin in animal cap explants activates siamois (sia) and nr3 but not gsc, indicating gsc requires additional mesodermal induction signals beyond Wnt/beta-catenin for activation and maintenance.\",\n      \"method\": \"Beta-catenin overexpression in animal cap explants, UV-irradiation to block cortical rotation, in situ hybridization for gsc/sia/nr3 markers across developmental stages\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment with gain-of-function and loss-of-function conditions using spatial marker analysis; single lab, two orthogonal approaches\",\n      \"pmids\": [\"9415495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In zebrafish, maternally deposited Lnx-2b restricts gsc expression to the dorsal mesoderm by limiting both Nodal signaling and Bozozok (Boz) activity; overexpression of Boz together with Lnx-2b depletion causes robust ectopic gsc expression in all blastomeres, demonstrating that Nodal signals are required for gsc expression even when Boz is elevated.\",\n      \"method\": \"Boz overexpression, Lnx-2b morpholino depletion, targeted single-cell injection at 128-cell stage, epistasis analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with double manipulation (overexpression + depletion), targeted cell injection; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"20971071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In porcine embryos, gsc expression localizes to one side of the embryoblast at day 10 and anterior to the primitive streak at day 13, consistent with its role as an early marker of the organizer/anterior mesendoderm in vertebrates.\",\n      \"method\": \"RT-PCR cloning of porcine gsc homeodomain region, in situ hybridization on whole-mount porcine embryos, relative expression quantification across days 9-13 of pregnancy\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, descriptive localization in a new species without functional consequence established; confirms conservation of expression pattern\",\n      \"pmids\": [\"10602267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ethanol-induced upregulation of GSC expression in human embryonic carcinoma cell-derived embryoid bodies is mediated by Nodal signaling, placing GSC downstream of Nodal in the context of ethanol teratogenicity during early embryonic differentiation.\",\n      \"method\": \"Chronic ethanol treatment of embryoid bodies, gene expression profiling, pathway analysis, Nodal signaling inhibitor experiments\",\n      \"journal\": \"Journal of applied toxicology : JAT\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway assignment based on pharmacological inhibition without direct mechanistic dissection of Nodal-GSC regulatory link\",\n      \"pmids\": [\"23378141\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GSC (goosecoid) is a homeodomain transcription factor that functions primarily as an active transcriptional repressor through a conserved eh1 domain shared with engrailed-class homeoproteins; it directly binds target gene promoters (e.g., ventx3.2) at defined Gsc response elements and recruits histone deacetylases via Foxh1 to repress target genes (e.g., Mixl1); its expression is activated downstream of integrated Nodal, Wnt, and maternal VegT/Siamois signals through cis-regulatory modules, and it functions as a necessary component of dorsal patterning in vertebrate gastrulation and definitive endoderm formation, with genetic interactions placing it upstream of Wnt/Dkk1 signaling in anterior head development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GSC (goosecoid) is a homeodomain transcription factor that acts as an active transcriptional repressor and serves as a necessary component of dorsal mesoderm patterning during vertebrate gastrulation and of definitive endoderm formation [#1, #6]. Its repressive activity depends on a conserved engrailed-homology (eh1) domain shared across en-, gsc-, Nk- and msh-class homeoproteins, which mediates active repression in vivo [#0]. Gsc binds defined response elements in target gene promoters and represses transcription directly: it occupies a Gsc response element in the BMP4 target ventx3.2, where point mutation of the element abolishes its repressive activity [#7], and it is recruited by Foxh1 into a DNA-binding complex that silences Mixl1 by engaging histone deacetylases [#3]. Loss of Gsc ventralizes Xenopus embryos and blocks LiCl-induced dorsalization [#1], and Gsc genetically interacts with Dkk1 to negatively regulate Wnt signaling during anterior head morphogenesis [#4]. gsc transcription itself is the integration point of multiple inductive inputs: stepwise binding of Siamois, VegT, Lim1/Lhx1, Otx2 and Mix1 at its cis-regulatory modules drives stage-specific expression [#5], with Wnt/\\u03b2-catenin necessary but not sufficient and Nodal signaling additionally required for activation [#9, #10]. In human embryonic stem cells, GSC is required for definitive endoderm differentiation and is regulated in trans by the lncRNA DIGIT [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the human GSC gene structure and its highly conserved homeodomain anchored goosecoid as a bona fide vertebrate homeobox transcription factor and provided a genomic locus for study.\",\n      \"evidence\": \"Genomic cloning, sequencing, and chromosomal mapping to 14q32.1\",\n      \"pmids\": [\"7916327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or DNA-binding activity demonstrated in this study\", \"Target genes unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Antisense loss-of-function showed that gsc is genuinely required for dorsal mesoderm patterning rather than merely correlated with it, placing it within the dorsalization pathway.\",\n      \"evidence\": \"Antisense RNA injection in Xenopus with marker analysis and LiCl/UV epistasis\",\n      \"pmids\": [\"7489713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets not identified\", \"Molecular mechanism of repression not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of the conserved eh1 repression domain explained how goosecoid-class homeoproteins act as active repressors in vivo, distinguishing this from cell-culture repression activities.\",\n      \"evidence\": \"In vivo homeodomain-swap retargeting, mutagenesis, and rescue transgenes\",\n      \"pmids\": [\"8898227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Corepressors engaged by eh1 not defined in this study\", \"Direct in vivo targets not mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Epistasis revealed that Wnt/\\u03b2-catenin alone cannot activate gsc, demonstrating it requires additional mesoderm-inducing signals and refining where gsc sits in the signaling hierarchy.\",\n      \"evidence\": \"\\u03b2-catenin overexpression in animal caps and UV cortical-rotation block in Xenopus\",\n      \"pmids\": [\"9415495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the additional inducing signal not pinned in this study\", \"Direct cis-elements not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Double-mutant genetics placed Gsc upstream of Dkk1/Wnt, framing it as a negative regulator of Wnt signaling in anterior head development.\",\n      \"evidence\": \"Gsc/Dkk1 double-mutant mice with Wnt reporter and in situ analysis\",\n      \"pmids\": [\"17127040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Gsc regulates Dkk1 directly not established\", \"No direct promoter binding shown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining the Foxh1-Gsc complex and HDAC recruitment provided a concrete molecular mechanism for Gsc repression of a specific target (Mixl1) and explained how Gsc reaches its DNA targets.\",\n      \"evidence\": \"Reciprocal Co-IP, Foxh1-null embryos, embryoid-body ectopic expression, HDAC recruitment assay in mouse\",\n      \"pmids\": [\"17568773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific HDAC isoform not identified\", \"Generalizability beyond Mixl1 not tested here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Zebrafish epistasis showed Nodal signaling is required for gsc expression even when Bozozok is elevated, clarifying the combinatorial maternal/zygotic inputs that spatially restrict gsc.\",\n      \"evidence\": \"Boz overexpression with Lnx-2b morpholino depletion and targeted single-cell injection\",\n      \"pmids\": [\"20971071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cis-regulatory targets of Nodal/Boz on gsc not mapped\", \"Cross-species applicability not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Stepwise occupancy of gsc CRMs by five transcription factors resolved how distinct inductive signals are integrated temporally to drive stage-specific gsc transcription.\",\n      \"evidence\": \"ChIP-qPCR for Siamois, VegT, Lim1, Otx2, Mix1 across developmental stages plus reporter assays in Xenopus\",\n      \"pmids\": [\"22492356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional necessity of each binding event not individually dissected\", \"Cofactors at CRMs not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that GSC is required for definitive endoderm differentiation of human ESCs and is controlled by the lncRNA DIGIT extended Gsc function to human endoderm specification and added a trans-regulatory layer.\",\n      \"evidence\": \"DIGIT deletion/depletion, GSC endogenous rescue, SMAD3 ChIP-seq, hESC differentiation assays\",\n      \"pmids\": [\"27705785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which DIGIT regulates GSC not fully resolved\", \"Direct GSC endoderm targets in human cells not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Inclusion of gsc in a TBP-family-insensitive transcription network with Gcn5 recruitment raised the possibility of non-canonical transcription initiation at the gsc locus.\",\n      \"evidence\": \"TBP-family triple-knockdown, \\u03b1-amanitin, transcriptome profiling, RNA Pol II/Gcn5 ChIP in Xenopus\",\n      \"pmids\": [\"26952988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Evidence for gsc-specific mechanism is indirect\", \"Functional consequence of Gcn5 recruitment not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genome-wide ChIP-seq with promoter mutagenesis demonstrated that Gsc directly binds a defined response element in the ventx3.2 promoter to repress this BMP4 target, providing direct in vivo evidence of sequence-specific Gsc repression.\",\n      \"evidence\": \"Gsc ChIP-seq, serial deletion/site-directed mutagenesis of ventx3.2 promoter, ChIP-PCR, marginal zone assays in Xenopus\",\n      \"pmids\": [\"38522664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors at the GRE not identified\", \"Full genome-wide target set not functionally validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Gsc's eh1 domain, Foxh1 partnership, and direct GRE binding are integrated into a unified repression mechanism across its full target repertoire, and whether human disease links exist, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No comprehensive genome-wide functional target map\", \"Corepressor complexes incompletely defined\", \"No Mendelian disease association established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FOXH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}