Affinage

ZIC2

Zinc finger protein ZIC 2 · UniProt O95409

Length
532 aa
Mass
55.0 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZIC2 is a zinc-finger transcription factor that functions as a master regulator of enhancer and promoter activity during embryonic patterning, neurulation, axon guidance, and stem cell state transitions. ZIC2 binds enhancers genome-wide and recruits chromatin remodeling complexes — NURF to activate OCT4 in liver cancer stem cells (PMID:26426078), Mbd3/NuRD to regulate differentiation-linked genes in ESCs (PMID:25699711), SWI/SNF to open primed-specific enhancers in hESCs (PMID:39358345), and ARID1A-BAF at EMT enhancers during neural crest specification (PMID:39226899) — while also modulating Wnt signaling through direct interaction with TCF4 and β-catenin (PMID:21908606, PMID:34099631), Hedgehog signaling through binding Gli1/Gli2 (PMID:21661123, PMID:21211521), and Nodal signaling through interaction with SMAD2/3 (PMID:27466203); DNA-PK-mediated phosphorylation at Ser200 drives a complex switch from DNA-PKcs/Ku/PARP to Ku/RNA helicase A, coupling ZIC2 to RNA polymerase II-dependent transcriptional activation (PMID:17251188, PMID:18068128). In neural development, ZIC2 controls midline axon guidance by inducing EphB1 and EphA4 expression in retinal ganglion cells and spinal neurons to direct ipsilateral projection (PMID:13678579, PMID:24360543), regulates neurulation timing and neural tube closure through BMP and RhoA pathways (PMID:10677508, PMID:36916392), and governs node ciliogenesis and left-right asymmetry via Nodal enhancer activation (PMID:24585447, PMID:29992973). Heterozygous loss-of-function mutations in ZIC2 cause holoprosencephaly in humans through a mechanism involving defective prechordal plate development at mid-gastrulation, independent of SHH signaling (PMID:9771712, PMID:18617531).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    The first causal link between ZIC2 and human disease was established when heterozygous loss-of-function mutations were shown to cause holoprosencephaly, identifying ZIC2 haploinsufficiency as a mechanism for brain malformations in 13q deletion patients.

    Evidence Molecular analysis of hemizygous deletions and mutation screening in HPE families

    PMID:9771712

    Open questions at the time
    • Molecular targets of ZIC2 in forebrain patterning unknown
    • Relationship to SHH pathway unclear
    • No mechanistic explanation for why haploinsufficiency is pathogenic
  2. 2000 High

    Mouse knockdown established that ZIC2 dosage controls the timing of neurulation and neural crest/roof plate differentiation, providing a developmental mechanism for the HPE and spina bifida phenotypes, while parallel studies demonstrated ZIC2 can function as both a transcriptional activator (APOE) and repressor (D1A dopamine receptor) depending on promoter context.

    Evidence Zic2 hypomorphic mouse model with in situ hybridization; yeast one-hybrid, EMSA, and luciferase reporter assays for D1A and APOE promoters

    PMID:10677508 PMID:10984499 PMID:11038359

    Open questions at the time
    • Direct transcriptional targets in neural tube closure unidentified
    • Domain architecture responsible for dual activator/repressor function unknown
  3. 2003 High

    ZIC2 was identified as a determinant of retinal axon laterality at the optic chiasm and shown to be required for neural crest production and hindbrain patterning, establishing its roles beyond forebrain development.

    Evidence Loss- and gain-of-function mouse experiments with retinal axon tracing; Zic2 mutant mice with lineage tracing of neural crest

    PMID:13678579 PMID:14651926

    Open questions at the time
    • Downstream guidance molecules regulated by Zic2 in RGCs not yet identified
    • Whether Zic2 acts cell-autonomously in neural crest unclear
  4. 2004 Medium

    Structure-function analysis revealed that ZIC2's C-terminus contains separable activation and repression domains, and that HPE-associated alanine-tract expansions alter DNA binding and transcriptional activity in a promoter-specific manner.

    Evidence In vitro transcriptional and DNA binding assays with mutant ZIC2 proteins

    PMID:15590697

    Open questions at the time
    • In vivo relevance of alanine-tract expansion not tested in animal models
    • Structural basis for promoter-specific effects unknown
  5. 2007 High

    A post-translational regulatory mechanism was uncovered: DNA-PK phosphorylates ZIC2 at Ser200, driving a switch from Complex I (DNA-PKcs/Ku/PARP) to Complex II (Ku/RNA helicase A), which then engages RNA Pol II for transcriptional activation.

    Evidence Co-immunoprecipitation, subnuclear fractionation, in vitro kinase assays; site-directed mutagenesis showing S200A mutant loses RHA binding

    PMID:17251188 PMID:18068128

    Open questions at the time
    • In vivo relevance of Ser200 phosphorylation in development not demonstrated
    • Target genes regulated through Complex I vs Complex II unknown
    • Structural basis for complex switching unclear
  6. 2008 High

    EphB1 was identified as a direct transcriptional target of ZIC2 in retinal ganglion cells, functionally sufficient to switch axon behavior from crossing to avoidance at the chiasm, while an EphB1-independent pathway also contributes; separately, ZIC2-associated HPE was shown to originate from a transient defect in the gastrula organizer/prechordal plate, independent of SHH signaling.

    Evidence In vivo gain/loss-of-function in mouse with axon tracing and EphB1 immunofluorescence; genetic epistasis with Shh compound mutants and PCP marker analysis

    PMID:18417618 PMID:18524895 PMID:18617531

    Open questions at the time
    • Identity of the EphB1-independent pathway unknown
    • How ZIC2 regulates prechordal plate gene expression mechanistically unresolved
  7. 2011 High

    ZIC2 was established as a signaling pathway modulator through direct protein-protein interactions: binding TCF4 to inhibit Wnt/β-catenin transcription, and binding Gli1/Gli2 to potentiate Hedgehog signaling, with the zinc finger domain mediating both interactions.

    Evidence Co-IP, luciferase reporters, Xenopus axis duplication assays (Wnt); Co-IP, subcellular fractionation, domain deletion (Gli); Myf5 enhancer assays and Gli2 Co-IP (somite context)

    PMID:21211521 PMID:21661123 PMID:21908606

    Open questions at the time
    • Whether ZIC2-TCF4 and ZIC2-Gli interactions occur simultaneously or in distinct contexts unclear
    • Genome-wide scope of Wnt and Hedgehog modulation by ZIC2 uncharacterized
  8. 2013 High

    ZIC2 was generalized as a CNS-wide determinant of ipsilateral axon trajectory by showing it induces EphA4 and represses Robo3 in dorsospinal neurons to prevent midline crossing.

    Evidence In vivo gain- and loss-of-function in mouse spinal cord with EphA4/Robo3 expression analysis

    PMID:24360543

    Open questions at the time
    • Direct transcriptional regulation of Robo3 by ZIC2 not demonstrated by ChIP
    • Whether the same mechanism applies in all CNS commissural systems unknown
  9. 2015 High

    Genome-wide binding studies revealed ZIC2 preferentially occupies enhancers in ESCs and EpiSCs, where it collaborates with Mbd3/NuRD (ESCs) and replaces SOX2/POU5F1 at enhancers during the transition to primed pluripotency, while in liver cancer stem cells ZIC2 recruits NURF to the OCT4 promoter to maintain self-renewal.

    Evidence ChIP-seq in ESCs showing enhancer enrichment and Mbd3/NuRD co-IP; ChIP-seq with biotinylated ZIC2 in EpiSCs; ChIP, sphere formation, and xenograft assays in liver CSCs

    PMID:25699711 PMID:26426078 PMID:28455373

    Open questions at the time
    • How ZIC2 selects between NURF and NuRD complexes at different loci unknown
    • Whether ZIC2 enhancer binding requires pioneer factor activity or pre-existing chromatin marks unclear
  10. 2016 High

    ZIC2 was linked to Nodal signaling through physical interaction with SMAD2/3 and cooperative regulation of FOXA2; HPE-associated ZIC2 variants were deficient in SMAD-dependent transcription, providing a molecular explanation for prechordal plate defects.

    Evidence Co-IP of ZIC2 with SMAD2/3, transcriptional reporter assays, Xenopus foxA2 regulation, functional analysis of HPE variant proteins

    PMID:27466203

    Open questions at the time
    • Genome-wide targets of ZIC2-SMAD cooperation not mapped
    • Whether SMAD interaction is zinc-finger-dependent like Gli/TCF4 binding unknown
  11. 2018 High

    ZIC2 was shown to directly regulate the Nodal enhancer HBE through a low-affinity binding site, integrating its roles in node ciliogenesis and Nodal transcription to establish left-right asymmetry; ZIC2 also directly activates Tgif1, another HPE gene.

    Evidence ChIP, enhancer site mutagenesis, in vitro transcription assays, 3D imaging of mouse mutants; ChIP and DNA binding assays for Tgif1

    PMID:24585447 PMID:29391420 PMID:29992973

    Open questions at the time
    • Whether ZIC2 regulation of Nodal and Tgif1 is coordinated in the same cells unknown
    • Low-affinity binding raises questions about how specificity is achieved in vivo
  12. 2020 High

    ZIC2 was found to switch Wnt5a signaling from a crossing-promoting to a repulsion mode in ipsilateral RGCs by regulating Wnt receptor expression, and was shown to be essential for cardiac progenitor specification through effects on early mesoderm; ZIC2 also directly represses STAT3 transcription.

    Evidence In vivo mouse gain/loss-of-function with Wnt pathway component analysis; CRISPR-KO screen in hPSCs with RNA-seq and scRNA-seq; ChIP-seq and siRNA in breast cancer cells

    PMID:32064600 PMID:32129551 PMID:33188033

    Open questions at the time
    • Identity of Wnt receptors directly regulated by ZIC2 at the transcriptional level not fully mapped
    • ZIC2 targets in cardiac mesoderm specification not individually validated
  13. 2023 High

    A dual mechanism for Zic2 mutant spina bifida was dissected: BMP signaling overactivation impairs dorsolateral hinge point formation while independent RhoA-dependent actomyosin accumulation disrupts neuroepithelium, each rescuable by distinct pharmacological inhibitors.

    Evidence Zic2Ku/Ku mouse mutant with dorsomorphin and Blebbistatin rescue in embryo culture

    PMID:36916392

    Open questions at the time
    • Whether ZIC2 directly transcriptionally represses BMP or RhoA pathway genes not shown
    • Relevance to human spina bifida genetics not established
  14. 2024 High

    ZIC2 was identified as a key effector of ARID1A-BAF at EMT enhancers in neural crest cells, with ARID1A haploinsufficiency causing ZIC2 to relocate to neuronal enhancers and aberrantly activate neuronal genes; separately, ZIC2/ZIC3 were shown to recruit SWI/SNF to open primed-specific enhancers in hESCs, placing ZIC2 as a chromatin remodeler recruiter at the ESC-to-primed transition.

    Evidence Patient-derived iPSC CNCC model with ATAC-seq/ChIP-seq, mouse conditional KO, chick electroporation; multi-omic hESC analysis with SWI/SNF degradation

    PMID:39226899 PMID:39358345

    Open questions at the time
    • Whether ZIC2 directly contacts ARID1A-BAF or acts through intermediaries not biochemically resolved
    • How ZIC2 selects between SWI/SNF, NuRD, and NURF at different enhancers remains an open question

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism by which ZIC2 selects among multiple chromatin remodeling complexes (NURF, NuRD, SWI/SNF, PRC2) at different genomic loci and in different cellular contexts remains unresolved, as does the structural basis for its dual activator/repressor functions and the in vivo relevance of DNA-PK-mediated complex switching.
  • No structural model of ZIC2 bound to DNA or protein partners
  • Genome-wide mapping of ZIC2 activator vs. repressor functions not performed
  • In vivo role of Ser200 phosphorylation in development untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 5
Partners
ARID1ACTNNB1DHX9GLI1GLI2SMAD2SMAD3TCF4
Complex memberships
DNA-PKcs/Ku70/Ku80/PARP (Complex I)Ku70/Ku80/RNA helicase A (Complex II)Mbd3/NuRDNURF

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Heterozygous loss-of-function mutations in ZIC2 cause holoprosencephaly (HPE) in humans; haploinsufficiency for ZIC2 is the likely mechanism for brain malformations seen in 13q deletion patients. Molecular analysis of hemizygous deletions, mutation screening, chromosomal mapping Nature genetics High 9771712
2000 Reduced expression (knockdown) of mouse Zic2 causes neurulation delay resulting in HPE and spina bifida, and delays differentiation of the dorsal neural plate (roof plate and neural crest cells), indicating Zic2 expression level is crucial for timing of neurulation. Zic2 hypomorphic knockdown mouse model, in situ hybridization for roof plate marker Wnt3a Proceedings of the National Academy of Sciences of the United States of America High 10677508
2000 ZIC2 binds to the activator region AR1 of the human D1A dopamine receptor gene promoter and represses Sp1-induced transcriptional activation in an AR1-dependent manner, acting antagonistically to Sp1. Yeast one-hybrid screening, gel shift assays, cotransfection luciferase reporter assays The Journal of biological chemistry Medium 10984499
2000 ZIC2 (and ZIC1) bind to specific sequences in the proximal APOE gene promoter and transactivate APOE expression, identified by yeast one-hybrid and confirmed by EMSA and cotransfection assays. Yeast one-hybrid screening, electrophoretic mobility shift assay (EMSA), cotransfection/luciferase reporter assays The Journal of biological chemistry Medium 11038359
2002 Zic2 cooperates with Zic1 to control cerebellar development by regulating neuronal differentiation and cell proliferation; compound Zic1(+/-)Zic2(+/kd) mice show cerebellar folial abnormalities with reduced cyclin D1 and increased p27/p16 expression in the external germinal layer. Compound mutant mouse genetics, in situ hybridization, immunohistochemistry for cell cycle markers The Journal of neuroscience High 11756505
2003 Zic2 is expressed in retinal ganglion cells (RGCs) with an uncrossed trajectory and is necessary and sufficient to regulate RGC axon repulsion at the optic chiasm midline, directing ipsilateral projection. Loss- and gain-of-function analyses in mouse, in vivo retinal axon tracing Cell High 13678579
2003 Zic2 mutation causes a delay in neural crest production and a decrease in neural crest cell number, and is required for normal hindbrain patterning (rhombomeres 3 and 5), independent of neuroectoderm mediolateral segmentation. Loss-of-function allele mouse genetics, in situ hybridization, lineage tracing Developmental biology High 14651926
2004 The C-terminal region of ZIC2 contains both activation and repression domains; alanine-tract expansion in ZIC2 modulates DNA binding strength and alters transcriptional activity in a promoter-specific manner, providing a mechanism for HPE-associated alanine-tract mutations. In vitro transcriptional activity assays, DNA binding assays with mutant ZIC2 proteins Human molecular genetics Medium 15590697
2007 ZIC2 forms two high-molecular-weight nuclear complexes: Complex I with DNA-PKcs, Ku70/80, and PARP; and Complex II with Ku70/80 and RNA helicase A (RHA). DNA-PK phosphorylates Zic2, driving exchange from Complex I to Complex II, which then interacts with RNA polymerase II for transcriptional regulation. Co-immunoprecipitation, subnuclear fractionation, in vitro phosphorylation assays The Journal of biological chemistry High 17251188
2007 Zic2 phosphorylation at serine 200 by DNA-dependent protein kinase is required for interaction with RNA helicase A and transcriptional activation; Zic2-S200A mutant is defective in RHA binding and has diminished transcriptional activation. Site-directed mutagenesis, co-immunoprecipitation, transcriptional reporter assays FEBS letters Medium 18068128
2008 Zic2 is necessary and sufficient in vivo to change RGC axon trajectory from crossed to uncrossed; Zic2 regulates EphB1 expression in RGCs, and an EphB1-independent pathway also contributes to retinal axon divergence at the midline. In vivo gain- and loss-of-function mouse experiments, retinal axon tracing, gene expression analysis Development (Cambridge, England) High 18417618
2008 Zic2 upregulates EphB1 mRNA and protein expression in retinal ganglion cells; ectopic Zic2 in non-VT retinal explants is sufficient to induce EphB1 protein localized to growth cones, functionally switching axon behavior from extension to avoidance of ephrinB2 substrates. Explant culture, ectopic Zic2 delivery, EphB1 protein localization by immunofluorescence, axon behavior assays on ephrinB2 substrates The Journal of neuroscience High 18524895
2008 Zic2-associated HPE is caused by a transient defect in the organizer region at mid-gastrulation, arresting prechordal plate (PCP) development; this is independent of Shh signaling, as molecular defects precede Shh signaling onset and Zic2 does not interact genetically with Shh to produce HPE. Mouse genetics, epistasis analysis (Zic2/Shh compound mutants), in situ hybridization for PCP markers Human molecular genetics High 18617531
2010 Zic2 controls the refinement of eye-specific inputs in visual targets by directly regulating expression of the serotonin transporter (Sert), which modulates activity-dependent mechanisms during wiring of sensory circuits. Gain-of-function Zic2 expression in RGCs, pharmacological Sert blockade, axonal refinement assays in visual targets The EMBO journal High 20676059
2011 ZIC2 directly binds the HMG box of TCF4 via its zinc finger domain and inhibits β-catenin·TCF4-mediated transcriptional activity without affecting TCF4 DNA binding; Zic2 injection in Xenopus blocks β-catenin-induced axis duplication, and Zic2 knockdown causes ectopic Wnt signaling at midbrain-hindbrain boundary. Co-immunoprecipitation, luciferase reporter assays, Xenopus axis duplication assay, transgenic Wnt reporter Xenopus embryos with morpholino knockdown The Journal of biological chemistry High 21908606
2011 Zic2 protein physically interacts with Gli1 and retains Gli1 in the nucleus, thereby increasing Gli-mediated transcriptional activity in cervical cancer cells; deletion of the C-terminal zinc finger domain of Zic2 abrogates this interaction. Co-immunoprecipitation, subcellular fractionation, immunofluorescence, luciferase reporter assay, domain deletion mutagenesis The Journal of pathology High 21661123
2011 Zic2 and Zic1 potentiate Gli-dependent Myf5 epaxial somite-specific enhancer transactivation; Zic2 co-immunoprecipitates with Gli2, forming complexes that promote Myf5 expression; Myf5 expression is delayed in Zic2 mutant embryos until Zic1 is activated. Functional reporter assays, co-immunoprecipitation, in situ hybridization in Zic2 mutant mice Developmental biology Medium 21211521
2013 Zic2 induces EphA4 expression in dorsospinal neurons to prevent midline crossing, and downregulates Robo3 to ensure axons enter dorsal tracts rather than growing ventrally; Zic2 acts as a general determinant of axon midline avoidance across CNS pathways. Gain- and loss-of-function experiments in vivo in mouse, gene expression analysis of EphA4 and Robo3 Neuron High 24360543
2014 Zic2 is transiently expressed in the mid-late gastrula node and is required for ciliogenesis there; Zic2 mutant embryos have dysmorphic, short node cilia, reduced expression of ciliogenesis regulators Noto, Rfx3, Foxj1, and Pkd1l1, leading to random cardiac situs. Mouse genetics, in situ hybridization for ciliogenesis genes, scanning electron microscopy/morphometry of cilia Genesis (New York, N.Y. : 2000) High 24585447
2015 ZIC2 acts upstream of OCT4 in liver cancer stem cells; ZIC2 recruits the NURF (nucleosome remodeling factor) complex to the OCT4 promoter, initiating OCT4 transcriptional activation and maintaining CSC self-renewal. ChIP, co-immunoprecipitation, sphere formation assay, xenograft tumor growth, siRNA knockdown The Journal of clinical investigation High 26426078
2015 Zic2 preferentially binds transcriptional enhancers genome-wide in embryonic stem cells and functions with Mbd3/NuRD complex to regulate chromatin state and transcriptional output of differentiation-linked genes, functioning as an enhancer-specific binding factor. ChIP-seq, genome-wide molecular studies, co-immunoprecipitation with Mbd3/NuRD, ESC differentiation assays Molecular cell High 25699711
2015 Zic2 controls migration of Cajal-Retzius cells, amygdaloid cells from caudal pallium, and cells from prethalamic neuroepithelium to the ventral lateral geniculate nucleus; Zic2-target EphB1 may partially mediate Zic2-dependent migratory events. Mouse mutant analysis, cell fate mapping, in vivo migration assays The Journal of neuroscience High 26269635
2016 ZIC2 physically interacts with SMAD2 and SMAD3 (NODAL pathway effectors); together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and Zic2 controls foxA2 expression in Xenopus; HPE-associated ZIC2 variant proteins are deficient in SMAD-dependent transcription, linking Zic2 to NODAL signaling in prechordal plate development. Co-immunoprecipitation, transcriptional reporter assays in cultured cells, Xenopus developmental assays, analysis of HPE variant proteins Human molecular genetics High 27466203
2017 Zic2 directly binds the PAK4 promoter (by ChIP and luciferase assay) and modulates its transcriptional activity; PAK4 then mediates Zic2-driven cell growth via the Raf/MEK/ERK pathway in hepatocellular carcinoma. ChIP, luciferase reporter assay, siRNA knockdown of PAK4, western blot for Raf/MEK/ERK pathway Cancer letters Medium 28577975
2017 ZIC2 localizes to the KSHV latent episome at immediate early/early gene cluster regions, interacts with and maintains Polycomb Repressive Complex 2 (PRC2) through physical interaction, preserving H3K27me3 marks at the K-Rta promoter and maintaining viral latency; the KSHV K-Rta protein ubiquitinates ZIC2 as an E3 ligase, targeting it for degradation to trigger viral reactivation. Co-immunoprecipitation, ChIP-seq, ubiquitination assays, ZIC2 depletion in naturally infected cells Journal of virology High 28835494
2017 ZIC2 in epiblast stem cells (EpiSCs) binds predominantly to enhancers; ChIP-seq reveals ZIC2 and OTX2 are the major acting transcription factors in EpiSCs (replacing SOX2/POU5F1 from ESCs), and ZIC2 primes relevant enhancers for activation during the ESC-to-EpiSC transition. ChIP-seq with in vivo biotinylated ZIC2, OTX2, SOX2, POU5F1, POU3F1 in EpiSCs Development (Cambridge, England) High 28455373
2018 ZIC2 is required for correct Nodal expression at the node through a low-affinity ZIC2 binding site in the Nodal enhancer HBE; ZIC2 acts at multiple levels to establish left-right asymmetry: promoting Nodal expression and the morphogenesis of cilia that bias Nodal distribution. ChIP-seq data analysis, in vitro transcriptional assays, site-directed mutagenesis of enhancer binding sites, 3D-imaging of mouse mutants Scientific reports High 29992973
2018 ZIC2 directly binds the Tgif1 promoter via Zic2-binding sites (ZBS) identified by ChIP and in vitro DNA binding assays, and ZBS are essential for Zic2-dependent transcriptional activation in reporter assays; Zic2 shows higher affinity to ZBS than GLI-binding sequences. Chromatin immunoprecipitation (ChIP), in vitro DNA binding assays, luciferase reporter assays Scientific reports Medium 29391420
2019 Zfp281 activates Zic2 at enhancers and promoters during exit from naive ESC state; Zic2 acts downstream of Zfp281 to drive exit from the naive ESC state and restricts reprogramming of EpiSCs, acting together with Ehmt1. Comparative CRISPR screening in ESCs and EpiSCs, chromatin binding analysis, genetic gain/loss-of-function The EMBO journal Medium 31782544
2020 Zic2 switches the Wnt5a-induced alternative Wnt pathway in ipsilateral retinal neurons by regulating expression of specific Wnt receptors and intracellular proteins; in combination with asymmetric EphB1 activation, phosphorylation of βcatenin elicits axon repulsion, while in contralateral neurons Wnt5a promotes crossing via βcatenin accumulation without canonical pathway activation. In vivo mouse gain/loss-of-function, molecular analysis of Wnt receptor/pathway component expression, biochemical pathway assays Science advances High 33188033
2020 ZIC2 is essential for cardiac progenitor formation from early mesodermal precursors; ZIC2-mutant hPSCs still express pluripotency markers but cannot differentiate into cardiomyocytes and switch to non-cardiac lineages; ZIC2 affects apelin receptor-related signaling during mesoderm formation. Genome-wide CRISPR-knockout screen, hPSC differentiation assays, RNA-seq, single-cell RNA-seq Stem cells (Dayton, Ohio) High 32129551
2020 ZIC2 binds the STAT3 promoter (by ChIP-seq) and represses STAT3 transcription; ZIC2 knockdown induces STAT3 expression and increases phosphorylated STAT3 levels in breast cancer cells. ChIP-seq, RNA-seq, luciferase reporter assay, siRNA knockdown International journal of cancer Medium 32064600
2020 SOX2 and ZIC2 cooperatively bind the D1 enhancer of Sox2 to activate it in the neural tube and neural crest; ZIC2 binding to the D1 enhancer is confirmed by chromatin immunoprecipitation in chick embryo. Chicken embryo electroporation, ChIP, mutagenesis of TF binding sites in enhancer Genes to cells Medium 31997540
2021 Zic2 directly binds the Axin2 promoter and transcriptionally represses Axin2 expression, promoting β-catenin accumulation and nuclear translocation; Zic2 also physically interacts with β-catenin to activate Wnt signaling in colon cancer cells. ChIP, luciferase reporter assay, co-immunoprecipitation, siRNA knockdown, xenograft models Cell death & disease Medium 34099631
2021 Silencing ZIC2 in NSCLC cells transcriptionally inhibits Src expression and inactivates FAK signaling, attenuating anoikis resistance; ZIC2 directly regulates Src at the transcriptional level (luciferase assay and ChIP). ChIP, luciferase reporter assay, siRNA knockdown, anchorage-independent growth assays Molecular therapy oncolytics Medium 34514099
2023 ZIC2 in NSCLC/NPC activates JUNB promoter directly (confirmed by ChIP-qPCR and luciferase assay) leading to MCSF secretion and M2 polarization of tumor-associated macrophages; blocking JUNB and MCSF reverses ZIC2-mediated M2 TAM polarization. ChIP-seq, ChIP-qPCR, luciferase reporter assay, cytokine secretion assays, macrophage polarization assays Cell death & disease Medium 37479694
2023 High ZIC2 expression in ccRCC is regulated by hypomethylation and H3K4Me3 at its promoter, and by positive transcriptional regulation by FOXM1; ZIC2 in turn transcriptionally activates UBE2C, activating the AKT/mTOR signaling pathway. ATAC-seq, MS-PCR, ChIP-PCR, luciferase reporter assay, RNA-seq International journal of biological sciences Medium 37496990
2023 Dual mechanism underlies Zic2 mutant (Kumba allele) spina bifida: BMP signaling overactivation causes failure of dorsolateral hinge point formation (rescued by dorsomorphin), and RhoA-dependent actomyosin accumulation impairs neuroepithelium (rescued by Blebbistatin); these two mechanisms are independent. Mouse Zic2Ku/Ku mutant, pharmacological rescue with dorsomorphin and Blebbistatin in embryo culture, immunofluorescence for actomyosin and BMP signaling markers Disease models & mechanisms High 36916392
2024 ARID1A-BAF chromatin remodeler binding at EMT-associated enhancers in cranial neural crest cells is impaired in ARID1A haploinsufficiency; these EMT enhancers contain ZIC2 binding motifs, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers causing aberrant neuronal gene activation; ZIC2 is required for neural crest cell delamination in mice and is sufficient to elicit ectopic delamination in chick. CSS patient-derived iPSC CNCC specification model, ATAC-seq, ChIP-seq, Zic2 conditional deletion in mouse neural crest, ZIC2 overexpression in chick embryo electroporation American journal of human genetics High 39226899
2024 ZIC2 and ZIC3 cooperatively open primed-specific enhancers in human ESCs by recruiting SWI/SNF chromatin remodeler; loss of ZIC2/3 prevents enhancer activation and results in transcriptome shifts toward mesendoderm differentiation genes and perturbed Polycomb activity. Multi-omic approach in hESC models, ATAC-seq, ChIP-seq, ZIC2/3 loss-of-function, SWI/SNF degradation experiments Nature communications High 39358345

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nature genetics 384 9771712
1997 The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation. Developmental biology 280 9070329
2003 Zic2 patterns binocular vision by specifying the uncrossed retinal projection. Cell 209 13678579
2000 Zic2 regulates the kinetics of neurulation. Proceedings of the National Academy of Sciences of the United States of America 196 10677508
2001 Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Human molecular genetics 148 11285244
2015 ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells. The Journal of clinical investigation 133 26426078
2004 Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations. Human mutation 120 15221788
2002 Zic2 controls cerebellar development in cooperation with Zic1. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 11756505
2003 Zic2 is required for neural crest formation and hindbrain patterning during mouse development. Developmental biology 105 14651926
2008 Zic2 promotes axonal divergence at the optic chiasm midline by EphB1-dependent and -independent mechanisms. Development (Cambridge, England) 89 18417618
2015 Zic2 is an enhancer-binding factor required for embryonic stem cell specification. Molecular cell 83 25699711
2008 Zic2-associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation. Human molecular genetics 75 18617531
2011 Transcription factor Zic2 inhibits Wnt/β-catenin protein signaling. The Journal of biological chemistry 70 21908606
2004 In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation. Human molecular genetics 70 15590697
2005 Frequency of SOX Group B (SOX1, 2, 3) and ZIC2 antibodies in Turkish patients with small cell lung carcinoma and their correlation with clinical parameters. Cancer 64 15880380
2009 Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. Journal of medical genetics 63 19955556
2013 Zic2-dependent axon midline avoidance controls the formation of major ipsilateral tracts in the CNS. Neuron 62 24360543
2017 Zic2 promotes tumor growth and metastasis via PAK4 in hepatocellular carcinoma. Cancer letters 59 28577975
2004 Overlapping and distinct expression domains of Zic2 and Zic3 during mouse gastrulation. Gene expression patterns : GEP 59 15261827
2008 Zic2 regulates retinal ganglion cell axon avoidance of ephrinB2 through inducing expression of the guidance receptor EphB1. The Journal of neuroscience : the official journal of the Society for Neuroscience 58 18524895
2010 Zic2 regulates the expression of Sert to modulate eye-specific refinement at the visual targets. The EMBO journal 57 20676059
2007 Zic2 and Zic3 synergistically control neurulation and segmentation of paraxial mesoderm in mouse embryo. Developmental biology 53 17490632
2009 The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism. Human mutation 52 19177455
2007 Array-based profiling of reference-independent methylation status (aPRIMES) identifies frequent promoter methylation and consecutive downregulation of ZIC2 in pediatric medulloblastoma. Nucleic acids research 51 17344319
2000 ZIC2 and Sp3 repress Sp1-induced activation of the human D1A dopamine receptor gene. The Journal of biological chemistry 51 10984499
2000 Transcription factors Zic1 and Zic2 bind and transactivate the apolipoprotein E gene promoter. The Journal of biological chemistry 50 11038359
2017 Long non-coding RNA HULC promotes bladder cancer cells proliferation but inhibits apoptosis via regulation of ZIC2 and PI3K/AKT signaling pathway. Cancer biomarkers : section A of Disease markers 48 28946549
2018 Upregulation of microRNA-129-5p inhibits cell invasion, migration and tumor angiogenesis by inhibiting ZIC2 via downregulation of the Hedgehog signaling pathway in cervical cancer. Cancer biology & therapy 47 30260270
2012 Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions. Molecular genetics and metabolism 47 22310223
2013 Site specific mutation of the Zic2 locus by microinjection of TALEN mRNA in mouse CD1, C3H and C57BL/6J oocytes. PloS one 46 23555929
2017 ChIP-seq analysis of genomic binding regions of five major transcription factors highlights a central role for ZIC2 in the mouse epiblast stem cell gene regulatory network. Development (Cambridge, England) 45 28455373
2012 The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 44 22733541
2011 Zic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells. The Journal of pathology 44 21661123
2003 Immunolocalization of Zic2 expression in the developing mouse forebrain. Gene expression patterns : GEP 43 12799086
2001 Behavioral abnormalities of Zic1 and Zic2 mutant mice: implications as models for human neurological disorders. Behavior genetics 43 11699604
2001 Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. Human genetics 42 11479728
2017 HOXA10 promotes nasopharyngeal carcinoma cell proliferation and invasion via inducing the expression of ZIC2. European review for medical and pharmacological sciences 41 28338202
2015 Addiction of pancreatic cancer cells to zinc-finger transcription factor ZIC2. Oncotarget 37 26318045
2019 Inactivation of the Wnt/β-catenin signaling pathway underlies inhibitory role of microRNA-129-5p in epithelial-mesenchymal transition and angiogenesis of prostate cancer by targeting ZIC2. Cancer cell international 33 31649488
2010 The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes. European journal of human genetics : EJHG 32 20531442
2019 MicroRNA-129-5p suppresses nasopharyngeal carcinoma lymphangiogenesis and lymph node metastasis by targeting ZIC2. Cellular oncology (Dordrecht, Netherlands) 31 31884576
2021 A Zic2/Runx2/NOLC1 signaling axis mediates tumor growth and metastasis in clear cell renal cell carcinoma. Cell death & disease 30 33767130
2011 A role for Zic1 and Zic2 in Myf5 regulation and somite myogenesis. Developmental biology 30 21211521
2007 ZIC2-dependent transcriptional regulation is mediated by DNA-dependent protein kinase, poly(ADP-ribose) polymerase, and RNA helicase A. The Journal of biological chemistry 30 17251188
2020 ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer. International journal of cancer 29 32064600
2016 Zic2 mutation causes holoprosencephaly via disruption of NODAL signalling. Human molecular genetics 29 27466203
2010 Expression of the zic1, zic2, zic3, and zic4 genes in early chick embryos. BMC research notes 28 20553611
2022 ZIC2 promotes colorectal cancer growth and metastasis through the TGF-β signaling pathway. Experimental cell research 27 35390314
2015 Zic2 Controls the Migration of Specific Neuronal Populations in the Developing Forebrain. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 26269635
2002 Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene. American journal of medical genetics 27 11857562
2019 Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2. The EMBO journal 26 31782544
2018 miR-1284 Inhibits the Growth and Invasion of Breast Cancer Cells by Targeting ZIC2. Oncology research 25 30075825
2018 miR‑1271‑5p inhibits cell proliferation and induces apoptosis in acute myeloid leukemia by targeting ZIC2. Molecular medicine reports 25 30483794
2004 Sequence relationships and expression patterns of zebrafish zic2 and zic5 genes. Gene expression patterns : GEP 25 15053986
2021 Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung cancer cells by inhibiting Src/FAK signaling. Molecular therapy oncolytics 24 34514099
2021 De novo ZIC2 frameshift variant associated with frontonasal dysplasia in a Limousin calf. BMC genomics 23 33388042
2020 Genome-wide CRISPR screen identifies ZIC2 as an essential gene that controls the cell fate of early mesodermal precursors to human heart progenitors. Stem cells (Dayton, Ohio) 23 32129551
2020 A Zic2-regulated switch in a noncanonical Wnt/βcatenin pathway is essential for the formation of bilateral circuits. Science advances 23 33188033
2008 Zic2 is expressed in pluripotent cells in the blastocyst and adult brain expression overlaps with makers of neurogenesis. Gene expression patterns : GEP 23 18755297
2017 ZIC2 promotes viability and invasion of human osteosarcoma cells by suppressing SHIP2 expression and activating PI3K/AKT pathways. Journal of cellular biochemistry 22 28857346
2020 ZIC2 promotes cancer stem cell traits via up-regulating OCT4 expression in lung adenocarcinoma cells. Journal of Cancer 21 32922547
2004 Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans. American journal of medical genetics. Part A 21 14679585
2021 Downregulation of LINC00665 suppresses the progression of lung adenocarcinoma via regulating miR-181c-5p/ZIC2 axis. Aging 20 34232917
2014 The Zic2 gene directs the formation and function of node cilia to control cardiac situs. Genesis (New York, N.Y. : 2000) 20 24585447
2011 Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2. American journal of medical genetics. Part A 20 21638761
2011 Zic2 hypomorphic mutant mice as a schizophrenia model and ZIC2 mutations identified in schizophrenia patients. Scientific reports 20 22355535
2021 Multilevel regulation of Wnt signaling by Zic2 in colon cancer due to mutation of β-catenin. Cell death & disease 19 34099631
2017 Zebrafish zic2 controls formation of periocular neural crest and choroid fissure morphogenesis. Developmental biology 19 28689736
2023 FOXM1-regulated ZIC2 promotes the malignant phenotype of renal clear cell carcinoma by activating UBE2C/mTOR signaling pathway. International journal of biological sciences 17 37496990
2021 ZIC2 upregulates lncRNA SNHG12 expression to promote endometrial cancer cell proliferation and migration by activating the Notch signaling pathway. Molecular medicine reports 17 34278490
2020 Sox2 gene regulation via the D1 enhancer in embryonic neural tube and neural crest by the combined action of SOX2 and ZIC2. Genes to cells : devoted to molecular & cellular mechanisms 17 31997540
2018 ZIC2 in Holoprosencephaly. Advances in experimental medicine and biology 15 29442327
2023 ZIC2 induces pro-tumor macrophage polarization in nasopharyngeal carcinoma by activating the JUNB/MCSF axis. Cell death & disease 14 37479694
2020 The tumor-suppressive role of microRNA-873 in nasopharyngeal carcinoma correlates with downregulation of ZIC2 and inhibition of AKT signaling pathway. Cancer gene therapy 13 32555352
2017 ZIC2 Is Essential for Maintenance of Latency and Is a Target of an Immediate Early Protein during Kaposi's Sarcoma-Associated Herpesvirus Lytic Reactivation. Journal of virology 13 28835494
2005 Neuronal cell type-specific promoter of the alpha CaM kinase II gene is activated by Zic2, a Zic family zinc finger protein. Neuroscience research 13 16157407
2007 Functional role of Zic2 phosphorylation in transcriptional regulation. FEBS letters 11 18068128
2024 ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial-to-mesenchymal transition in cranial neural crest specification. American journal of human genetics 9 39226899
2022 Silencing of circDPP4 suppresses cell progression of human prostate cancer and enhances docetaxel cytotoxicity through regulating the miR-564/ZIC2 axis. The journal of gene medicine 9 34904327
2022 KLF17 promotes human naive pluripotency through repressing MAPK3 and ZIC2. Science China. Life sciences 9 35391627
2012 Unique alterations of an ultraconserved non-coding element in the 3'UTR of ZIC2 in holoprosencephaly. PloS one 9 22859937
2011 Duplication of the ZIC2 gene is not associated with holoprosencephaly. American journal of medical genetics. Part A 9 22105922
2024 ZIC2 and ZIC3 promote SWI/SNF recruitment to safeguard progression towards human primed pluripotency. Nature communications 8 39358345
2018 A Requirement for Zic2 in the Regulation of Nodal Expression Underlies the Establishment of Left-Sided Identity. Scientific reports 8 29992973
2018 Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice. Scientific reports 7 29463853
2014 Rare nasal cleft in a patient with holoprosencephaly due to a mutation in the ZIC2 gene. Birth defects research. Part A, Clinical and molecular teratology 7 24677696
2012 Comparison of mutation findings in ZIC2 between microform and classical holoprosencephaly in a Brazilian cohort. Birth defects research. Part A, Clinical and molecular teratology 6 22847929
2018 Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression. Scientific reports 5 29391420
2018 Roles of ZIC2 in Regulation of Pluripotent Stem Cells. Advances in experimental medicine and biology 5 29442330
2014 Holoprosencephaly: ZIC2 mutation in a case with panhypopituitarism. Journal of pediatric endocrinology & metabolism : JPEM 5 24706429
2023 Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse. Disease models & mechanisms 4 36916392
2023 ZIC2 accelerates growth and stemness in gastric cancer through the Wnt/β-catenin pathway. Tissue & cell 4 37774522
2022 The long noncoding RNA LINC00200 promotes the malignant progression of MYCN-amplified neuroblastoma via binding to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) to enhance the stability of Zic family member 2 (ZIC2) mRNA. Pathology, research and practice 4 35969939
2021 De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family. International journal of molecular sciences 4 33557041
2019 Case report: a novel mutation in ZIC2 in an infant with microcephaly, holoprosencephaly, and arachnoid cyst. Medicine 4 30855487
2011 Holoprosencephaly and ZIC2 microdeletions: novel clinical and epidemiological specificities delineated. Clinical genetics 4 21496007
2008 No association of the polyhistidine tract polymorphism of the ZIC2 gene with neural tube defects in a South American (ECLAMC) population. Molecular medicine reports 4 21479430
2024 Actin filament-associated protein 1-antisense RNA1 promotes the development and invasion of tongue squamous cell carcinoma via the AFAP1-AS1/miR-133a-5p/ZIC2 axis. The journal of gene medicine 3 38282153
2024 Transcription factor ZIC2 regulates the tumorigenic phenotypes associated with both bulk and cancer stem cells in epithelial ovarian cancer. Oncogene 2 38594503
2020 Middle interhemispheric variant of holoprosencephaly: First prenatal report of a ZIC2 missense mutation. Clinical case reports 2 32695376