Affinage

GCM1

Chorion-specific transcription factor GCMa · UniProt Q9NP62

Length
436 aa
Mass
49.3 kDa
Annotated
2026-06-10
58 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCM1 (GCMa) is a placenta-specific, zinc-containing transcription factor that serves as a master regulator of trophoblast differentiation, being essential for labyrinthine placental development and trophoblast cell-fate restriction (PMID:10713170, PMID:15196947). It binds GCM-binding sites in target promoters and directly activates a differentiation program, most notably the fusogenic syncytin-1 and syncytin-2 genes and the syncytin-2 receptor MFSD2A, driving syncytiotrophoblast formation and cell fusion (PMID:12397062, PMID:20484742, PMID:15864327). In human trophoblast stem cells, GCM1 is required for differentiation into both syncytiotrophoblast and extravillous trophoblast (EVT) lineages, in part through activation of CKMT1 and CDKN1C and through antagonism with ΔNp63α governing the stemness-versus-differentiation switch (PMID:35338152, PMID:36442132, PMID:40280139). GCM1 promotes EVT migration and invasion by transcriptionally activating WNT10B, which signals via FZD7 and Rac1 (PMID:29979633), and it directs chorionic branching morphogenesis through a positive feedback loop with Fzd5/β-catenin signaling (PMID:23610556). GCM1 activity is governed by an extensive post-translational network: cAMP/PKA promotes CBP-mediated acetylation at Lys367/406/409 that stabilizes the transactivation domain against ubiquitination (PMID:16166624), a parallel cAMP/Epac1/CaMKI pathway phosphorylates Ser47 to recruit SENP1 for activating desumoylation (PMID:21791615), while hypoxia-activated GSK-3β phosphorylates Ser322 to recruit the SCF(FBW2) ubiquitin ligase (with UBE2D2 as E2) for proteasomal degradation (PMID:15640526, PMID:19416964, PMID:18703417), a fate opposed by DUSP23 and by RACK1 competition for FBW2 (PMID:20855292, PMID:23651062). GCM1 is further tuned by repressive partners including HDAC3, caspase-14, GATA3, DLX3, and the transcriptional inputs of CREB/OASIS, Twist1, and DREAM (PMID:16528103, PMID:23580611, PMID:26899996, PMID:28515447, PMID:18495750, PMID:26992674, PMID:23300953). Beyond placentation, folate deficiency drives Gcm1 induction and assembly of a Gcm1/β-catenin/TCF4 complex that activates aberrant Wnt signaling implicated in neural tube defects (PMID:33664222, PMID:41217685).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established that GCM1 is genetically essential for placental development, defining its biological importance before its molecular targets were known.

    Evidence Constitutive knockout mouse with histological analysis of labyrinthine placenta

    PMID:10713170

    Open questions at the time
    • Did not identify direct transcriptional targets
    • Did not address human placental function
  2. 2002 High

    Identified the first direct GCM1 target by showing it binds syncytin promoter GCM-sites and drives trophoblast cell fusion, linking GCM1 to syncytiotrophoblast formation.

    Evidence Reporter, adenoviral overexpression, and cell fusion assays in trophoblast vs HeLa cells

    PMID:12397062

    Open questions at the time
    • Cell-type specificity of GCM1 activity not mechanistically explained
    • In vivo relevance to human syncytialization not tested
  3. 2004 Medium

    Defined GCM1 as a cell-fate restrictor that arrests trophoblast stem cell proliferation and channels cells toward the syncytiotrophoblast pathway.

    Evidence Overexpression and antisense knockdown in trophoblast stem cells

    PMID:15196947

    Open questions at the time
    • Downstream effectors of proliferation arrest not identified
    • Antisense specificity limited
  4. 2005 High

    Resolved the core post-translational control of GCM1 stability: SCF(FBW2)-mediated ubiquitination targets GCM1 for degradation while PKA-driven CBP acetylation stabilizes it, framing GCM1 abundance as a balance of opposing modifications.

    Evidence Co-IP, in vivo ubiquitination, RNAi, pulse-chase, in vitro acetylation, mutagenesis of Lys367/406/409

    PMID:15640526 PMID:15864327 PMID:16166624

    Open questions at the time
    • Upstream signals selecting acetylation vs degradation not yet defined
    • Phospho-degron recognized by FBW2 not yet mapped
  5. 2006 High

    Showed that HDAC-mediated deacetylation directly counteracts CBP coactivation at GCM1 target promoters, establishing dynamic acetylation as a switch for target gene activation.

    Evidence GST pull-down, ChIP showing forskolin-dependent HDAC3 dissociation from syncytin promoter, reporter assays

    PMID:16528103

    Open questions at the time
    • How HDAC recruitment is signaled remains unclear
    • Relative roles of HDAC1/3/4/5 not dissected in vivo
  6. 2009 High

    Connected environmental hypoxia to GCM1 turnover by mapping a GSK-3β phospho-degron at Ser322 that recruits FBW2, explaining how oxygen tension regulates trophoblast differentiation.

    Evidence Cell phosphorylation/ubiquitination assays, Ser322 mutagenesis, LiCl inhibition under hypoxia

    PMID:19416964

    Open questions at the time
    • Quantitative link between physiological hypoxia and placental GCM1 levels in vivo not established
  7. 2010 High

    Expanded the GCM1 regulon and refined its stability control by identifying syncytin-2/MFSD2A as direct targets and DUSP23 as a phosphatase that reverses the Ser322 degron to stabilize GCM1.

    Evidence EMSA, ChIP, cell fusion assays; Co-IP and RNAi for DUSP23

    PMID:20484742 PMID:20855292

    Open questions at the time
    • Proposed CpG demethylation role for GCM1 not mechanistically resolved
    • DUSP23 regulation upstream not defined
  8. 2011 Medium

    Identified a desumoylation arm of GCM1 activation via cAMP/Epac1/CaMKI-driven Ser47 phosphorylation recruiting SENP1, showing multiple parallel cAMP pathways converge to activate GCM1.

    Evidence RNAi, phosphomimetic rescue, GCM1-SENP1 Co-IP, cell fusion with Epac activator

    PMID:21558372 PMID:21791615

    Open questions at the time
    • SUMO acceptor site(s) on GCM1 not fully mapped
    • Crosstalk between acetylation and desumoylation arms not quantified
  9. 2013 Medium

    Placed GCM1 within developmental signaling and invasion circuits, defining a Gcm1/Fzd5/β-catenin feedback loop for chorionic branching and a RACK1/FBW2 competition that stabilizes GCM1 to support trophoblast migration.

    Evidence Tissue-specific mouse knockouts, tetraploid aggregation; TAP-MS, Co-IP, invasion assays; DREAM EMSA/ChIP promoter studies

    PMID:23300953 PMID:23580611 PMID:23610556 PMID:23651062

    Open questions at the time
    • Integration of branching loop with stability network not unified
    • DREAM and caspase-14 inputs not linked to in vivo phenotypes
  10. 2016 Medium

    Demonstrated that homeodomain and GATA transcription factors directly bind GCM1 to restrain its activity, establishing protein-protein repression as a layer of GCM1 control over invasion genes.

    Evidence Co-IP with domain mapping, reporter and invasion assays for GATA3; ChIP/Twist1 upstream

    PMID:26899996 PMID:26992674

    Open questions at the time
    • Combinatorial logic among repressors not resolved
    • Physiological context selecting each repressor unknown
  11. 2018 Medium

    Defined a transcriptional mechanism for GCM1-driven EVT migration through WNT10B-FZD7-Rac1, with decidual SFRP3 providing maternal-side negative control.

    Evidence Reporter assays, siRNA, migration/invasion assays, co-culture with decidual stromal cells

    PMID:29979633

    Open questions at the time
    • In vivo requirement of WNT10B downstream of GCM1 not tested
    • Rac1 effectors mediating motility not identified
  12. 2022 Medium

    Generalized GCM1 function to human trophoblast stem cells, showing it is required for both STB and EVT differentiation via antagonism with ΔNp63α and activation of CKMT1, anchoring earlier mouse and cell-line findings in human biology.

    Evidence hTSC knockdown, STB/EVT differentiation assays, reporter assays, RNA-seq

    PMID:35338152 PMID:36442132

    Open questions at the time
    • Mechanism of GCM1/ΔNp63α mutual antagonism not structurally defined
    • How GCM1 balances the two lineage outputs unclear
  13. 2025 Medium

    Extended the GCM1 target repertoire to CDKN1C governing contact inhibition and identified LINC01118 as a stabilizing partner, while implicating Gcm1/β-catenin/TCF4 in folate-deficiency neural tube defects beyond the placenta.

    Evidence CRISPR KO with ChIP and contact inhibition assays; RNA-IP and stability assays; folate-deficiency cell and mouse NTD models with Gcm1 ChIP-seq

    PMID:33664222 PMID:40280139 PMID:41117589 PMID:41217685

    Open questions at the time
    • Extraplacental Gcm1 expression and function not fully characterized
    • Direct contribution of GCM1 to human NTDs not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dozens of activating and repressive inputs are temporally and spatially integrated to produce the precise STB-versus-EVT decision in human placentation remains unresolved.
  • No unified quantitative model of competing PTMs and partners
  • No structural basis for GCM1-cofactor selectivity
  • Genome-wide direct target map in human trophoblast incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3
Partners
CBPDUSP23FBXW2GATA3HDAC3RACK1SENP1UBE2D2
Complex memberships
GCM1/β-catenin/TCF4 complexSCF(FBW2) E3 ubiquitin ligase (substrate)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GCMa (GCM1) transcriptionally activates syncytin gene expression via two GCMa-binding sites upstream of the 5'-LTR of the syncytin-harboring HERV-W family member, specifically in trophoblast cells (BeWo and JEG3) but not HeLa cells; adenovirus-directed GCMa expression enhanced syncytin expression and syncytin-mediated cell fusion. Transient transfection, adenovirus-directed expression, reporter assays in BeWo/JEG3 vs. HeLa cells The Journal of biological chemistry High 12397062
2000 Genetic ablation of murine GCMa (mGCMa) causes embryonic lethality due to placental failure; mutant placentas lack a functional labyrinth layer and labyrinthine trophoblasts fail to differentiate, establishing GCMa as essential for trophoblast differentiation in labyrinthine placenta. Conditional/constitutive knockout mouse model, histological and morphological analysis Molecular and cellular biology High 10713170
2005 cAMP/PKA signaling activates GCM1 transcriptional activity by promoting CBP-mediated acetylation of GCM1 at Lys367, Lys406, and Lys409 in the transactivation domain; acetylation protects GCM1 from ubiquitination and increases TAD stability and transcriptional activity. Co-immunoprecipitation, in vitro acetylation assays, site-directed mutagenesis, reporter assays, PKA treatment of placental cells Molecular and cellular biology High 16166624
2005 The F-box protein FBW2 (hFBW2) acts as the substrate recognition subunit in the SCF E3 ubiquitin ligase complex for hGCMa; FBW2 interacts with GCM1 in a phosphorylation-dependent manner and promotes GCM1 ubiquitination and proteasomal degradation; SKP1 and CUL1 also associate with GCM1 in vivo. Co-immunoprecipitation, in vivo ubiquitination assay, RNAi knockdown of FBW2, pulse-chase experiments The Journal of biological chemistry High 15640526
2006 HDAC3 directly interacts with GCMa and deacetylates it, counteracting CBP's coactivation of GCMa-mediated transcription; HDAC1, 3, 4, and 5 interact with and deacetylate GCMa; HDAC3 associates with the proximal GCMa-binding site in the syncytin promoter and dissociates upon forskolin treatment. GST pull-down assays, chromatin immunoprecipitation (ChIP), reporter assays, TSA inhibitor experiments, Co-immunoprecipitation Nucleic acids research High 16528103
2009 Hypoxia triggers GCM1 degradation by suppressing the PI3K-Akt pathway, leading to GSK-3β activation; activated GSK-3β phosphorylates GCM1 on Ser322, recruiting F-box protein FBW2 and leading to GCM1 ubiquitination and proteasomal degradation; GSK-3β inhibitor LiCl prevents this degradation. Cell-based phosphorylation assays, ubiquitination assays, site-directed mutagenesis (Ser322), pharmacological inhibition (LiCl), Western blot in hypoxic conditions The Journal of biological chemistry High 19416964
2010 GCM1 regulates syncytin 2 and its cognate receptor MFSD2A expression in placental cells via functional GCM1-binding sites identified in their promoters; GCM1 may also mediate epigenetic regulation of syncytin 2 gene expression via CpG demethylation. Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), ectopic GCM1 expression in MCF-7 cells, cell fusion assay Biology of reproduction High 20484742
2011 GCM1 is desumoylated via a novel cAMP/Epac1/CaMKI signaling pathway: Epac1 and Rap1 activate CaMKI to phosphorylate GCM1 at Ser47, facilitating GCM1 interaction with the SUMO protease SENP1 and leading to GCM1 desumoylation and activation; this promotes syncytin-1 and -2 expression and placental cell fusion. RNAi knockdown, phosphomimetic mutant rescue, reporter assays, co-immunoprecipitation (GCM1-SENP1 interaction), cell fusion assay with 8-CPT-AM Epac activator Molecular and cellular biology High 21791615
2010 Dual-specificity phosphatase 23 (DUSP23) interacts with GCM1 in a manner enhanced by PKA-dependent phosphorylation of GCM1 on Ser269 and Ser275; DUSP23 dephosphorylates GSK-3β-mediated Ser322 phosphorylation on GCM1, promoting GCM1 acetylation, stabilization, and activation; DUSP23 knockdown suppresses GCM1 target gene expression and placental cell fusion. Co-immunoprecipitation, phosphorylation assays, RNAi knockdown, reporter assays, cell fusion assay Nucleic acids research High 20855292
2008 UBE2D2 is the E2 ubiquitin-conjugating enzyme required for SCF(FBXW2)-mediated GCM1 ubiquitination; UBE2D2 enzyme activity is required for GCM1 ubiquitination and for association with the SCF(FBXW2) complex; knockdown of UBE2D2 reduces GCM1 ubiquitination and prolongs GCM1 half-life in vivo. In vitro ubiquitination assay, RNAi knockdown, co-immunoprecipitation, pulse-chase assay Biology of reproduction High 18703417
2004 Gcm1 induces rapid arrest of trophoblast stem (TS) cell proliferation and blocks trophoblast giant cell differentiation; antisense Gcm1 transcript blocks syncytiotrophoblast differentiation, establishing Gcm1 as a cell-fate restrictor toward the syncytiotrophoblast pathway. Ectopic overexpression of Gcm1 in TS cells, antisense knockdown, cell proliferation and differentiation assays in presence/absence of FGF4/CM Developmental biology Medium 15196947
2013 GCM1 and Frizzled 5 (Fzd5) form a positive feedback loop: Gcm1 upregulates Fzd5 at sites of branching initiation in the basal chorion, and elevated Fzd5 via nuclear β-catenin signaling in turn maintains Gcm1 expression; Fzd5-mediated signaling induces disassociation of cell junctions by downregulating ZO-1, claudin 4, and claudin 7 in trophoblast cells, and upregulates Vegf. Global and trophoblast-specific Fzd5-null and Gcm1-deficient mouse models, trophoblast stem cell lines, tetraploid aggregation assay, Western blot, immunofluorescence PLoS biology High 23610556
2016 GATA3 physically interacts with GCM1 (but not GCM2) through GCM1's DNA-binding domain and first transcriptional activation domain, and through GATA3's transcriptional activation domains and zinc finger 1 domain; GATA3 suppresses GCM1 transcriptional activity without affecting DNA binding, thereby inhibiting HtrA4 promoter activity and trophoblastic invasion. Co-immunoprecipitation, domain-mapping by deletion mutants, reporter assays, GATA3 knockdown, trophoblast invasion assay Scientific reports Medium 26899996
2005 Recombinant hGCMa/1 protein (from baculovirus-insect cell or E. coli systems) mediates specific transcriptional activation in vitro on a native syncytin promoter; a TATA box downstream of the proximal GBS in the syncytin promoter is essential for GCMa/1-mediated transcriptional activation. In vitro transcription system with G-free reporter constructs, recombinant protein preparation from baculovirus/E. coli Biochemistry and cell biology High 15864327
2003 Nuclear localization of GCMa/Gcm-1 is mediated by two atypical regions: one corresponding to the amino-terminal part of the GCM domain, and a second tyrosine-and-proline-rich carboxy-terminal region; nuclear import is counteracted by an amino-terminal nuclear export activity. This differs from GCMb/Gcm-2 which uses a classical bipartite NLS. Deletion mutagenesis, GFP-fusion constructs, nuclear localization assay by immunofluorescence/microscopy FEBS letters Medium 14572643
2007 GCMa/Gcm1 directly regulates expression of integrin-α4, Rb1, and syncytin A in murine placenta, as shown by their significant downregulation in GCMa-deficient chorionic tissue; promoter studies confirmed GCMa-dependent regulation of integrin-α4 and Rb1. Microarray (gene expression profiling of GCMa-deficient vs wild-type chorion), qRT-PCR validation, promoter reporter assays, in situ hybridization The Journal of biological chemistry Medium 18167345
2004 Pitx transcription factors interact with GCMa via their conserved homeodomain binding to the DNA-binding domain of GCMa; this interaction leads to cooperative DNA binding; Pitx proteins influence GCMa-dependent promoter activation in a cell-specific manner; Pitx2 colocalizes with GCMa in kidney. Co-immunoprecipitation, GST pull-down, electrophoretic mobility shift assay (EMSA) for cooperative DNA binding, reporter assays, immunofluorescence colocalization The Journal of biological chemistry Medium 15385555
2013 RACK1 interacts with FBW2 via WD repeats and competes with GCM1 for FBW2 binding, thereby preventing GCM1 ubiquitination and stabilizing GCM1; RACK1 knockdown destabilizes GCM1, decreases HtrA4 expression, and reduces BeWo cell migration and invasion. Tandem-affinity purification coupled with MS, Co-immunoprecipitation, RNAi knockdown, cell migration/invasion assay The Biochemical journal Medium 23651062
2013 DREAM (calcium-regulated transcriptional repressor) directly binds to the GCM1 promoter and represses GCM1 expression; siRNA-mediated DREAM silencing upregulates GCM1 expression and reduces cytotrophoblast proliferation; DREAM binding to the GCM1 promoter is calcium-dependent. EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown in cell culture and placental explant, ionomycin treatment (calcium dependency) PloS one Medium 23300953
2013 Caspase-14 proenzyme interacts with GCM1 and impedes the interaction between GCM1 and CBP, thereby suppressing CBP-mediated acetylation and transcriptional coactivation of GCM1, leading to inhibition of placental cell differentiation. Tandem affinity purification coupled with mass spectrometry, Co-immunoprecipitation, RNAi knockdown of caspase-14, reporter assays, cell fusion assay FASEB journal Medium 23580611
2018 GCM1 promotes extravillous trophoblast (EVT) cell migration through transcriptional activation of WNT10B; WNT10B signals via Frizzled 7 (FZD7) to stimulate cytoskeletal remodeling via Rac1; decidual SFRP3 blocks the WNT10B-FZD7 interaction to negatively modulate EVT migration. Reporter assays (GCM1 transactivation of WNT10B promoter), siRNA knockdown, cell migration/invasion assay, immunohistochemistry, co-culture with decidualized stromal cells FASEB journal Medium 29979633
2011 PKA signaling activates GCMa by promoting CBP-mediated GCMa acetylation and SENP-mediated GCMa desumoylation; p45NF-E2 negatively regulates Gcm1 and syncytiotrophoblast formation in mouse trophoblast cells via acetylation; absence of p45NF-E2 increases Gcm1 expression and leads to spontaneous syncytiotrophoblast formation reversible by Gcm1 knockdown. p45NF-E2 knockout mouse model, Gcm1 knockdown rescue experiment, acetylation inhibition/stimulation in vivo Development (Cambridge, England) Medium 21558372
2011 PMA induces GCMa phosphorylation at Ser328, Ser378, and Ser383 via a PKC- and MEK/ERK-dependent pathway, leading to GCM1 ubiquitination and proteasomal degradation. Pharmacological PKC and MEK inhibitors, site-directed mutagenesis (Ser328/378/383), Western blot, ubiquitination assay in JEG-3 cells Biochemical and biophysical research communications Medium 22206674
2016 Twist1 binds to an E-box-enriched region in intron 2 of the GCM1 gene during trophoblast syncytialization; siRNA-mediated silencing of Twist1 inhibits BeWo cell fusion and downregulates GCM1 expression, indicating Twist1 acts upstream of GCM1 to promote syncytialization. Chromatin immunoprecipitation (ChIP), siRNA knockdown of Twist1, cell fusion assay, qPCR/Western blot Placenta Medium 26992674
2008 CREB and OASIS (bZIP transcription factors) bind to CRE sites in the GCMa promoter (CREB at -1337) and stimulate GCMa transcription in trophoblast cells; TORC1 co-activator of CREB upregulates the GCMa promoter; CREB expression is replaced by OASIS around E12.5 during placentation; CREB or OASIS knockdown decreases endogenous GCMa mRNA levels. Reporter assays, EMSA, promoter deletion/mutation analysis, siRNA knockdown, ectopic TORC1/OASIS overexpression Nucleic acids research Medium 18495750
2017 DLX3 physically interacts with GCM1 via the DLX3 homeodomain, and this interaction inhibits GCM1 transactivation activity; the DLX3 homeodomain together with the amino- or carboxyl-terminal domains is required for maximal inhibition; DLX3 and GCM1 co-occupy the PGF promoter regulatory region as shown by ChIP. Co-immunoprecipitation, mammalian one-hybrid assay, deletion mutagenesis, ChIP assay at PGF promoter Scientific reports Medium 28515447
2017 Both DLX3 and GCM1 are positive regulators of placental growth factor (PGF) expression in trophoblast cells; they co-occupy a regulatory element in the PGF promoter identified by deletion and mutagenesis studies; co-expression of DLX3 and GCM1 leads to an antagonistic effect on PGF expression. Overexpression/knockdown reporter assays, chromatin immunoprecipitation (ChIP), site-directed mutagenesis of PGF promoter Journal of cellular physiology Medium 27996093
2022 ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation, establishing a functional antagonism controlling trophoblast stemness vs. differentiation; GCM1 knockdown blocks both syncytiotrophoblast and EVT differentiation from human trophoblast stem cells; GCM1 transcriptionally activates CKMT1 as a target gene critical for syncytiotrophoblast differentiation. Trophoblast stem cell knockdown experiments, STB/EVT differentiation assays, reporter assays, Western blot, RNA sequencing Nature communications Medium 35338152
2022 GCM1 knockdown in human trophoblast stem cells hinders differentiation into both syncytiotrophoblast and extravillous trophoblast pathways; GCM1-deficient cells show decreased expression of EVT-associated genes and increased WNT signaling, linked to decreased ASCL2 and NOTUM expression. GCM1 knockdown in human TS cells, STB/EVT differentiation assays, RNA sequencing, invasion assay through matrix Proceedings of the National Academy of Sciences of the United States of America Medium 36442132
2025 GCM1 knockout in human trophoblast stem cells impairs EVT and STB differentiation; chromatin immunoprecipitation of GCM1 showed binding near CDKN1C (contact inhibition factor); loss of GCM1 results in downregulation of CDKN1C and loss of contact inhibition. CRISPR knockout of GCM1 in hTSC, STB/EVT differentiation assays, ChIP of GCM1, cell contact inhibition assay Stem cell reports Medium 40280139
2021 GCM1 forms a complex with β-catenin and TCF4, promoting Wnt target gene transactivation; folate deficiency promotes formation of this Gcm1/β-catenin/TCF4 complex and activates aberrant Wnt/β-catenin signaling, contributing to neural tube defects. Co-immunoprecipitation, reporter assays with Wnt-responsive elements, folate-deficiency cell model, mouse NTD model Cell death & disease Medium 33664222
2025 LINC01118 lncRNA directly interacts with GCM1 protein, enhancing its protein stability and transcriptional activity; this supports GCM1 autoregulation and downstream target gene expression for trophoblast fusion and hormone production. RNA immunoprecipitation, protein stability assay, reporter assay, TS cell STB differentiation model FASEB journal Medium 41117589
2025 Folate deficiency upregulates Gcm1 expression through H4 acetylation enrichment in its promoter, mediated by CBP; Gcm1 ChIP-seq identified Lef1 as a downstream target of Gcm1, linking Gcm1 to aberrant Wnt/β-catenin pathway activation in NTDs. ChIP-qPCR for H4 acetylation, Co-IP (Gcm1-CBP interaction), Gcm1-ChIP-seq, mouse NTD model, human NTD sample NanoString analysis Molecular neurobiology Medium 41217685

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 GCMa regulates the syncytin-mediated trophoblastic fusion. The Journal of biological chemistry 228 12397062
2000 Placental failure in mice lacking the mammalian homolog of glial cells missing, GCMa. Molecular and cellular biology 165 10713170
2006 The natural history of the WRKY-GCM1 zinc fingers and the relationship between transcription factors and transposons. Nucleic acids research 127 17130173
2004 The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to promote terminal differentiation of trophoblast stem cells. Developmental biology 124 15196947
1999 Murine Gcm1 gene is expressed in a subset of placental trophoblast cells. Developmental dynamics : an official publication of the American Association of Anatomists 121 10213386
2005 Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions. FEBS letters 113 16004993
2010 GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biology of reproduction 98 20484742
2013 A positive feedback loop involving Gcm1 and Fzd5 directs chorionic branching morphogenesis in the placenta. PLoS biology 83 23610556
2004 Complex patterns of GCM1 mRNA and protein in villous and extravillous trophoblast cells of the human placenta. Placenta 82 15135239
2005 Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa. Molecular and cellular biology 75 16166624
2022 The multifaceted role of GCM1 during trophoblast differentiation in the human placenta. Proceedings of the National Academy of Sciences of the United States of America 73 36442132
2009 Mechanism of hypoxia-induced GCM1 degradation: implications for the pathogenesis of preeclampsia. The Journal of biological chemistry 68 19416964
2006 Histone deacetylase 3 binds to and regulates the GCMa transcription factor. Nucleic acids research 67 16528103
1996 Gcm1, a mammalian homolog of Drosophila glial cells missing. FEBS letters 60 8814290
2012 Effects of reduced Gcm1 expression on trophoblast morphology, fetoplacental vascularity, and pregnancy outcomes in mice. Hypertension (Dallas, Tex. : 1979) 57 22275534
2020 SP1-activated long noncoding RNA lncRNA GCMA functions as a competing endogenous RNA to promote tumor metastasis by sponging miR-124 and miR-34a in gastric cancer. Oncogene 49 32439864
2005 FBW2 targets GCMa to the ubiquitin-proteasome degradation system. The Journal of biological chemistry 45 15640526
2022 Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation. Nature communications 44 35338152
2011 A novel cyclic AMP/Epac1/CaMKI signaling cascade promotes GCM1 desumoylation and placental cell fusion. Molecular and cellular biology 44 21791615
2002 Gcm1 expression defines three stages of chorio-allantoic interaction during placental development. Mechanisms of development 39 12049764
2016 GATA3 inhibits GCM1 activity and trophoblast cell invasion. Scientific reports 37 26899996
2010 Dual-specificity phosphatase 23 mediates GCM1 dephosphorylation and activation. Nucleic acids research 33 20855292
2008 bZIP-Type transcription factors CREB and OASIS bind and stimulate the promoter of the mammalian transcription factor GCMa/Gcm1 in trophoblast cells. Nucleic acids research 33 18495750
2016 Twist1 is involved in trophoblast syncytialization by regulating GCM1. Placenta 31 26992674
2002 Restricted expression of mouse GCMa/Gcm1 in kidney and thymus. Mechanisms of development 31 12351183
2011 p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth. Development (Cambridge, England) 29 21558372
2021 Induction of the PPARγ (Peroxisome Proliferator-Activated Receptor γ)-GCM1 (Glial Cell Missing 1) Syncytialization Axis Reduces sFLT1 (Soluble fms-Like Tyrosine Kinase 1) in the Preeclamptic Placenta. Hypertension (Dallas, Tex. : 1979) 27 34024123
2006 Increased plasma mRNAs of placenta-specific 1 (PLAC1) and glial cells-missing 1 (GCM1) in mothers with pre-eclampsia. Hiroshima journal of medical sciences 27 16594548
2005 Biochemical characterization of the human placental transcription factor GCMa/1. Biochemistry and cell biology = Biochimie et biologie cellulaire 26 15864327
2007 Identification of integrin-alpha4, Rb1, and syncytin a as murine placental target genes of the transcription factor GCMa/Gcm1. The Journal of biological chemistry 25 18167345
2009 CD9 regulates transcription factor GCM1 and ERVWE1 expression through the cAMP/protein kinase A signaling pathway. Reproduction (Cambridge, England) 23 19692500
2008 Ubiquitin-conjugating enzyme UBE2D2 is responsible for FBXW2 (F-box and WD repeat domain containing 2)-mediated human GCM1 (glial cell missing homolog 1) ubiquitination and degradation. Biology of reproduction 23 18703417
2013 DREAM mediated regulation of GCM1 in the human placental trophoblast. PloS one 22 23300953
2020 NPFF increases fusogenic proteins syncytin 1 and syncytin 2 via GCM1 in first trimester primary human cytotrophoblast cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 32501590
2017 p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction. Cell death & disease 17 28383551
2021 Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects. Cell death & disease 16 33664222
2017 Dlx3 and GCM-1 functionally coordinate the regulation of placental growth factor in human trophoblast-derived cells. Journal of cellular physiology 16 27996093
2013 RACK1 (receptor for activated C-kinase 1) interacts with FBW2 (F-box and WD-repeat domain-containing 2) to up-regulate GCM1 (glial cell missing 1) stability and placental cell migration and invasion. The Biochemical journal 16 23651062
2002 Ectopic expression of Gcm1 induces congenital spinal cord abnormalities. Development (Cambridge, England) 16 12135932
2004 Interaction, cooperative promoter modulation, and renal colocalization of GCMa and Pitx2. The Journal of biological chemistry 15 15385555
2017 Relevance of Wnt10b and activation of β-catenin/GCMa/syncytin-1 pathway in BeWo cell fusion. American journal of reproductive immunology (New York, N.Y. : 1989) 14 28370659
2000 Genomic organization, chromosomal localization, and the complete 22 kb DNA sequence of the human GCMa/GCM1, a placenta-specific transcription factor gene. Biochemical and biophysical research communications 13 11071865
2017 DLX3 interacts with GCM1 and inhibits its transactivation-stimulating activity in a homeodomain-dependent manner in human trophoblast-derived cells. Scientific reports 12 28515447
2019 Gcm1 is involved in cell proliferation and fibrosis during kidney regeneration after ischemia-reperfusion injury. Scientific reports 11 31133638
2011 A fetal variant in the GCM1 gene is associated with pregnancy induced hypertension in a predominantly hispanic population. International journal of molecular epidemiology and genetics 11 21915358
2018 SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 29979633
2013 Caspase-14 suppresses GCM1 acetylation and inhibits placental cell differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 23580611
2009 Hypoxia upregulates GCM1 in human placenta explants. Hypertension in pregnancy 10 19843007
2011 PMA induces GCMa phosphorylation and alters its stability via the PKC- and ERK-dependent pathway. Biochemical and biophysical research communications 8 22206674
2016 Ex vivo culture of pre-placental tissues reveals that the allantois is required for maintained expression of Gcm1 and Tpbpα. Placenta 6 27780534
2003 Structural requirements for nuclear localization of GCMa/Gcm-1. FEBS letters 6 14572643
2025 Hypoxia and loss of GCM1 expression prevent differentiation and contact inhibition in human trophoblast stem cells. Stem cell reports 5 40280139
2020 Correction: SP1-activated long noncoding RNA lncRNA GCMA functions as a competing endogenous RNA to promote tumor metastasis by sponging miR-124 and miR-34a in gastric cancer. Oncogene 3 32913198
2012 PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation. Biomedical research (Tokyo, Japan) 3 22975632
2024 Hypoxia and loss of GCM1 expression prevents differentiation and contact inhibition in human trophoblast stem cells. bioRxiv : the preprint server for biology 2 39314437
2025 Functional Interaction of GCM1 and LINC01118 Regulates Syncytiotrophoblast Differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41117589
2025 Gcm1 Orchestrates Lef1 Expression in Folate Deficiency-Induced Neural Tube Defects. Molecular neurobiology 0 41217685
2025 Evolution and expression of glial cells missing (GCM1 and GCM2) in monotremes suggest an ancient role in reproduction. Open biology 0 41537828

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