Affinage

ZIC2

Zinc finger protein ZIC 2 · UniProt O95409

Length
532 aa
Mass
55.0 kDa
Annotated
2026-06-11
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZIC2 is a dosage-sensitive zinc finger transcription factor that patterns the embryonic forebrain midline, neural tube, and binocular visual system, and regulates stem cell state transitions through enhancer-directed control of gene expression (PMID:9771712, PMID:13678579, PMID:25699711). Heterozygous loss-of-function mutations cause holoprosencephaly, and reduced Zic2 dosage delays neurulation and dorsal neural plate differentiation, producing spina bifida (PMID:9771712, PMID:10677508). ZIC2's forebrain function operates downstream of NODAL signaling: it physically interacts with the receptor-activated transducers SMAD2 and SMAD3 to control FOXA2 transcription during prechordal plate development, and HPE-associated variants are deficient in SMAD-dependent transcription (PMID:27466203, PMID:18617531). The zinc finger domain mediates both DNA binding and protein-protein interactions, and its integrity is essential for transcriptional activity (PMID:15590697, PMID:22355535). In the visual system, ZIC2 is necessary and sufficient to specify ipsilateral retinal ganglion cell identity by directly inducing EphB1 to drive midline axon repulsion, and it further shapes circuit assembly by inducing EphA4, downregulating Robo3, controlling the serotonin transporter Sert, and rewiring non-canonical Wnt5a signaling (PMID:13678579, PMID:18417618, PMID:18524895, PMID:24360543, PMID:20676059, PMID:33188033). ZIC2 intersects multiple morphogen pathways as a context-dependent activator or repressor: it binds the HMG box of TCF4 to inhibit β-catenin·TCF4 transcription, interacts with Gli1/Gli2 to modulate Hedgehog output, and binds a low-affinity Nodal enhancer to drive node Nodal expression for left-right axis determination (PMID:21908606, PMID:21661123, PMID:21211521, PMID:29992973). Genome-wide, ZIC2 preferentially occupies enhancers and works with chromatin machinery—the Mbd3/NuRD complex, NURF, and SWI/SNF—to set chromatin state and prime or activate cell-state-specific enhancers governing pluripotency exit and differentiation (PMID:25699711, PMID:26426078, PMID:39358345, PMID:28455373). Its enhancer occupancy is directed by partner factors, including stabilization by Zfp281 and ARID1A-BAF-dependent targeting to EMT enhancers during cranial neural crest specification (PMID:31782544, PMID:39226899). In cancer contexts ZIC2 acts as an enhancer/promoter-binding regulator of diverse targets including OCT4, PAK4, STAT3, Axin2, Src, and RUNX2 (PMID:26426078, PMID:28577975, PMID:32064600, PMID:34099631, PMID:34514099, PMID:37496990).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1998 High

    Established ZIC2 as a dosage-sensitive transcription factor required for forebrain development by linking haploinsufficiency to a human malformation syndrome.

    Evidence Deletion mapping and direct ZIC2 sequencing in holoprosencephaly patients

    PMID:9771712

    Open questions at the time
    • Did not define direct transcriptional targets
    • Mechanism of dosage sensitivity not resolved
  2. 2000 High

    Showed that Zic2 expression level controls the timing of neurulation, explaining how reduced dosage produces both HPE and spina bifida.

    Evidence Hypomorphic Zic2 knockdown mouse with roof plate marker analysis

    PMID:10677508

    Open questions at the time
    • Molecular pathway linking Zic2 to neurulation timing not identified
    • Direct targets in the neural plate unknown
  3. 2000 Medium

    First identified ZIC2 as a sequence-specific DNA-binding transcription factor capable of both repression and activation at defined promoters.

    Evidence Yeast one-hybrid, EMSA, and reporter assays on D1A dopamine receptor and APOE promoters

    PMID:10984499 PMID:11038359

    Open questions at the time
    • In vitro promoter assays without developmental context
    • Endogenous relevance of these targets not established
  4. 2002 High

    Demonstrated cooperative, dosage-dependent control of cerebellar neuronal differentiation by Zic genes through cell-cycle regulators.

    Evidence Compound Zic1/Zic2 mutant mouse genetics with cell-cycle marker analysis

    PMID:11756505

    Open questions at the time
    • Direct vs indirect regulation of cyclin D1/p27/p16 not distinguished
  5. 2003 High

    Defined Zic2 as the determinant of ipsilateral retinal ganglion cell identity, providing a mechanism for binocular circuit formation.

    Evidence Bidirectional loss- and gain-of-function in mouse with axon tracing

    PMID:13678579 PMID:14651926

    Open questions at the time
    • Downstream guidance effectors not yet identified at this stage
  6. 2004 Medium

    Mapped activation/repression domains and showed the C-terminal alanine tract modulates DNA binding and links HPE mutations to altered ZIC2 function.

    Evidence In vitro transcription and DNA-binding assays with alanine-tract mutants

    PMID:15590697

    Open questions at the time
    • Promoter-specific effects not tested in vivo
    • Structural basis of alanine-tract modulation unresolved
  7. 2007 High

    Revealed that Zic2 transcriptional activity is regulated by DNA-PK phosphorylation at Ser200, driving exchange between DNA-PK/PARP and RNA helicase A nuclear complexes coupled to RNA Pol II.

    Evidence Co-IP, subnuclear fractionation, in vitro phosphorylation, and S200A mutagenesis with reporter assays

    PMID:17251188 PMID:18068128

    Open questions at the time
    • In vivo relevance of these complexes in development not tested
    • Target genes regulated by this switch unknown
  8. 2008 High

    Identified EphB1 as a direct, functional Zic2 target mediating axon repulsion, while showing an EphB1-independent divergence arm also exists.

    Evidence Retinal explant electroporation with EphB1 detection, ephrinB2 avoidance assays, and mouse genetics

    PMID:18417618 PMID:18524895

    Open questions at the time
    • EphB1-independent pathway effectors not defined
  9. 2008 High

    Pinpointed the developmental origin of Zic2-associated HPE to transient organizer/prechordal plate failure at gastrulation, upstream and independent of Shh.

    Evidence Mouse genetics with prechordal plate markers and Shh-pathway epistasis

    PMID:18617531

    Open questions at the time
    • Upstream signal placing Zic2 in the organizer not yet defined at this point
  10. 2010 High

    Extended Zic2 control beyond axon guidance to activity-dependent axonal refinement via direct regulation of the serotonin transporter.

    Evidence Gain-of-function electroporation with pharmacological Sert blockade and refinement assays

    PMID:20676059

    Open questions at the time
    • Mechanism linking Sert to refinement only partly defined
  11. 2011 Medium

    Positioned ZIC2 as a node intersecting Wnt and Hedgehog signaling through direct protein interactions with TCF4 and Gli proteins.

    Evidence Co-IP with domain mapping, reporter assays, Xenopus axis duplication, and PSM explants

    PMID:21211521 PMID:21661123 PMID:21908606

    Open questions at the time
    • Context-dependence of activator vs repressor outcomes unresolved
    • Single-lab interaction data for Gli partners
  12. 2013 High

    Generalized the ipsilaterality program beyond the retina by showing Zic2 induces EphA4 and represses Robo3 to route dorsospinal and thalamocortical axons.

    Evidence Bidirectional in vivo genetics with axon tracing and gene expression analysis

    PMID:24360543

    Open questions at the time
    • Directness of Robo3 repression not fully established
  13. 2014 Medium

    Identified a role for Zic2 in node ciliogenesis and left-right axis determination through upstream control of ciliogenesis regulators.

    Evidence Mouse genetics with electron microscopy and in situ analysis of Noto/Rfx3/Foxj1/Pkd1l1

    PMID:24585447

    Open questions at the time
    • Directness of ciliogenesis gene regulation unknown
    • Single-lab morphological study
  14. 2015 High

    Established ZIC2 as a genome-wide enhancer-binding factor that partners with chromatin machinery (Mbd3/NuRD, NURF) to control differentiation and stem cell self-renewal.

    Evidence ChIP-seq, biochemical co-purification, and loss-of-function in ESCs and liver cancer stem cells

    PMID:25699711 PMID:26426078

    Open questions at the time
    • How ZIC2 selects activating vs repressive chromatin outcomes unresolved
  15. 2015 Medium

    Linked Zic2 enhancer activity to neuronal migration programs, with EphB1 mediating part of the migratory phenotype.

    Evidence Conditional/hypomorphic mouse mutants with in vivo cell tracking and electroporation

    PMID:26269635

    Open questions at the time
    • EphB1-independent migratory effectors not defined
  16. 2016 High

    Defined the molecular link between NODAL signaling and ZIC2 by showing direct SMAD2/3 interaction and joint regulation of FOXA2, explaining prechordal plate HPE.

    Evidence Reciprocal Co-IP, FOXA2 reporter assays, Xenopus assays, and HPE-variant mutagenesis

    PMID:27466203

    Open questions at the time
    • Genome-wide SMAD/ZIC2 co-occupancy not mapped
  17. 2017 Medium

    Identified an endogenous chromatin-repressive role for ZIC2 in tethering PRC2 and maintaining H3K27me3, while also being a target of viral ubiquitination.

    Evidence Co-IP, ubiquitination assay, and ChIP-seq in KSHV-infected cells

    PMID:28835494

    Open questions at the time
    • Whether ZIC2-PRC2 tethering operates at developmental loci unknown
  18. 2017 Medium

    Expanded the cancer-relevant target repertoire by showing direct ZIC2 promoter binding and activation of PAK4 feeding into Raf/MEK/ERK.

    Evidence ChIP, reporter assays, and knockdown/rescue in hepatocellular carcinoma

    PMID:28577975

    Open questions at the time
    • Single-cancer-context study
    • Directness of pathway coupling partly inferred
  19. 2018 Medium

    Showed ZIC2 binds a low-affinity Nodal node enhancer to activate Nodal and initiate the left-determining cascade, and directly regulates the HPE gene Tgif1.

    Evidence ChIP-seq, in vitro binding/transcription assays, binding-site mutagenesis, and mouse mutant analysis

    PMID:29391420 PMID:29992973

    Open questions at the time
    • Affinity hierarchy between ZBS and GLI sites only partly characterized in vivo
  20. 2018 Medium

    Connected zinc finger domain integrity to ZIC2 function by showing a schizophrenia-associated R409P mutation impairs DNA and cofactor binding and activation.

    Evidence In vitro reporter, DNA-binding, and cofactor-binding assays with the mutant

    PMID:22355535

    Open questions at the time
    • Causal contribution to disease not established
    • In vivo consequences untested
  21. 2019 Medium

    Defined how ZIC2 is recruited to chromatin during pluripotency exit, with Zfp281 stabilizing it at enhancers/promoters and Ehmt1 acting downstream.

    Evidence CRISPR screening, genetic epistasis, and chromatin binding analysis in ESCs/EpiSCs

    PMID:28455373 PMID:31782544

    Open questions at the time
    • Biochemical basis of Zfp281-ZIC2 stabilization not resolved
  22. 2020 Medium

    Broadened the ZIC2 axon-guidance program to include non-canonical Wnt5a rewiring acting with EphB1 to phosphorylate β-catenin for repulsion.

    Evidence Bidirectional in vivo genetics with transcriptomics and axon tracing

    PMID:33188033

    Open questions at the time
    • Which Wnt receptors are direct ZIC2 targets not fully defined
  23. 2020 Medium

    Established ZIC2 as a context-dependent regulator of multiple cancer pathways, repressing STAT3 in breast cancer while being required for cardiac progenitor differentiation.

    Evidence ChIP-seq/RNA-seq with rescue in breast cancer, and genome-wide CRISPR screen in hPSCs

    PMID:32064600 PMID:32129551

    Open questions at the time
    • Determinants of tumor-suppressive vs oncogenic ZIC2 behavior unresolved
  24. 2020 Medium

    Demonstrated combinatorial enhancer activation by SOX2 and ZIC2 at the Sox2 D1 enhancer in neural tube and neural crest.

    Evidence Chicken embryo electroporation with binding-site mutagenesis and ChIP

    PMID:31997540

    Open questions at the time
    • Endogenous requirement vs sufficiency not fully separated
  25. 2021 Medium

    Showed multilevel ZIC2 enhancement of Wnt/β-catenin signaling in colon cancer by repressing Axin2 and binding β-catenin, with additional activation of Src and SNHG12 targets.

    Evidence ChIP, Co-IP, reporter, and functional assays across colon, lung, and endometrial cancer models

    PMID:34099631 PMID:34278490 PMID:34514099

    Open questions at the time
    • Apparent opposite Wnt regulation vs TCF4 inhibition not mechanistically reconciled
  26. 2023 Medium

    Linked upstream epigenetic and transcriptional control of ZIC2 (hypomethylation, H3K4me3, FOXM1) to downstream RUNX2 activation and immune modulation via JUNB.

    Evidence RNA-seq/ATAC-seq/ChIP-PCR/methylation analysis in ccRCC and NPC tumor models

    PMID:37479694 PMID:37496990

    Open questions at the time
    • Single-cancer-context mechanisms
    • Generalizability of upstream regulation unknown
  27. 2024 High

    Resolved how partner chromatin remodelers direct ZIC2 enhancer occupancy: ARID1A-BAF targets ZIC2 to EMT enhancers in cranial neural crest, and ZIC2/ZIC3 recruit SWI/SNF to activate primed-pluripotency enhancers.

    Evidence ChIP-seq/ATAC-seq in patient iPSC-derived CNCCs and hESCs, with bidirectional in vivo genetics and SWI/SNF degradation

    PMID:39226899 PMID:39358345

    Open questions at the time
    • How ZIC2 toggles between EMT and neuronal enhancer programs not fully defined
    • Direct ZIC2-SWI/SNF contact surface unmapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The rules governing whether ZIC2 acts as an activator or repressor at a given enhancer—and how it integrates NODAL, Wnt, and Hedgehog inputs with specific chromatin remodeler partners in each developmental and cancer context—remain unresolved.
  • No unified model linking partner choice to activation vs repression
  • Context-specific direct target sets incompletely mapped
  • Phosphorylation switch not connected to defined developmental loci

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6 GO:0140097 catalytic activity, acting on DNA 3
Localization
GO:0000228 nuclear chromosome 5 GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
ARID1AGLI1GLI2SMAD2SMAD3SOX2TCF4ZFP281
Complex memberships
Mbd3/NuRDNURFPRC2SWI/SNF (BAF)

Evidence

Reading pass · 42 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); haploinsufficiency for ZIC2 is sufficient to cause brain malformations, establishing ZIC2 as a dosage-sensitive transcription factor required for forebrain development. Molecular analysis of chromosome 13q32 deletions and direct sequencing of ZIC2 in HPE patients Nature genetics High 9771712
2000 Reduced Zic2 expression (knockdown) in mice causes neurulation delay resulting in HPE and spina bifida, and delays differentiation of the dorsal neural plate (roof plate and neural crest), demonstrating that Zic2 expression level is critical for the timing of neurulation. Hypomorphic Zic2 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 and Sp3 repress Sp1-induced transcriptional activation of the human D1A dopamine receptor gene in an AR1 activator region-dependent manner; ZIC2 was identified by yeast one-hybrid screening as a factor binding AR1. Yeast one-hybrid screening, gel shift assays (EMSA), cotransfection luciferase reporter assays The Journal of biological chemistry Medium 10984499
2000 Zic1 and Zic2 bind to specific sequences in the apolipoprotein E gene promoter (regions -185/-174, -136/-125, -65/-54) and transactivate APOE gene expression. Yeast one-hybrid screening, EMSA, mutational analysis, cotransfection luciferase reporter assays, endogenous APOE protein measurement The Journal of biological chemistry Medium 11038359
2002 Zic2 and Zic1 cooperatively control cerebellar development by regulating neuronal differentiation; compound Zic1+/-/Zic2+/kd mice show cerebellar folial abnormalities with reduced cell proliferation in the external germinal layer, reduced cyclin D1, and enhanced p27/p16 expression. Compound mutant mouse genetics, in situ hybridization for zonal markers, immunohistochemistry for cell cycle regulators The Journal of neuroscience High 11756505
2003 Zic2 is expressed in retinal ganglion cells (RGCs) with an uncrossed ipsilateral trajectory; loss- and gain-of-function analyses demonstrate that Zic2 is necessary and sufficient for RGC axon repulsion by cues at the optic chiasm midline, specifying the uncrossed retinal projection. In situ hybridization, immunofluorescence, loss-of-function (Zic2 mutant mice), gain-of-function (in vivo electroporation), 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); these defects are independent of mediolateral segmentation or dorsal neurectoderm proliferation. Loss-of-function Zic2 allele (null); in situ hybridization for neural crest and hindbrain markers Developmental biology High 14651926
2004 The C-terminal region of ZIC2 contains both activation and repression domains; the C-terminal alanine tract modulates DNA binding strength and transcriptional activity in a promoter-specific manner, and expansion of the alanine tract associated with HPE alters ZIC2 function. In vitro transcriptional activity assays, DNA binding assays with alanine-tract length mutants, analysis of HPE-associated mutations Human molecular genetics Medium 15590697
2007 ZIC2-dependent transcriptional regulation involves two high-molecular-weight nuclear complexes: Complex I contains DNA-PKcs, Ku70/80, and PARP; Complex II contains Ku70/80 and RNA helicase A (RHA). DNA-PK phosphorylates Zic2, driving stepwise exchange from Complex I to Complex II; phosphorylated Zic2 forms a stable complex with RHA which can interact with RNA Pol II. Co-immunoprecipitation, subnuclear fractionation, in vitro phosphorylation assay, protein complex characterization The Journal of biological chemistry High 17251188
2007 Serine 200 of Zic2 is a phosphorylation site targeted by DNA-PK; S200A mutation abolishes RNA helicase A (RHA) binding and diminishes transcriptional activation capacity, establishing phosphorylation-dependent regulation of Zic2 transcriptional activity. Site-directed mutagenesis, co-immunoprecipitation, transcriptional reporter assay FEBS letters Medium 18068128
2008 Zic2 is required and sufficient to change RGC axon trajectories from crossed to uncrossed; Zic2 regulates EphB1 expression in RGCs (an EphB1-dependent pathway), and also controls axon divergence via an EphB1-independent pathway. In vivo gain- and loss-of-function in mouse (electroporation, Zic2 mutants), EphB1 protein expression analysis, axon tracing Development (Cambridge, England) High 18417618
2008 Ectopic delivery of Zic2 into non-ventrotemporal retinal explants induces EphB1 mRNA and protein expression in growth cones, and the upregulated EphB1 is functional, switching RGC axon behavior from extension onto to avoidance of ephrinB2 substrates, establishing a direct link between Zic2 transcription factor activity and EphB1-mediated guidance receptor expression. Retinal explant electroporation, immunofluorescence for EphB1 protein in growth cones, ephrinB2 substrate avoidance assay The Journal of neuroscience High 18524895
2008 Zic2-associated HPE is caused by a transient defect in organizer region function at mid-gastrulation, causing arrest in prechordal plate (PCP) development; this defect precedes the onset of Shh signaling and Zic2 does not interact with Shh to produce HPE. Mouse genetics (Zic2 mutants), molecular marker analysis of prechordal plate, genetic epistasis with Shh pathway mutants Human molecular genetics High 18617531
2010 Zic2 controls eye-specific axonal refinement at visual targets by directly regulating expression of the serotonin transporter (Sert); RGCs ectopically expressing Zic2 show defects in axonal refinement and respond to pharmacological blockade of Sert, whereas Zic2-negative contralateral RGCs do not. Gain-of-function electroporation, pharmacological Sert blockade, axon refinement assays, ChIP/promoter analysis The EMBO journal High 20676059
2011 ZIC2 binds directly to the DNA-binding HMG box of TCF4 via its zinc finger domain and inhibits β-catenin·TCF4-mediated transcription without affecting TCF4 DNA binding; Zic2 RNA injection blocks β-catenin-induced axis duplication in Xenopus and inhibits Wnt target gene expression. Co-immunoprecipitation, luciferase reporter assays, Xenopus axis duplication assay, morpholino knockdown in transgenic Wnt reporter Xenopus The Journal of biological chemistry High 21908606
2011 Zic2 physically interacts with Gli1 and retains Gli1 in the nucleus, increasing Gli-mediated transcriptional activity; deletion of the C-terminal zinc finger domain of Zic2 abrogates Gli1 interaction and nuclear retention, as well as oncogenic properties in cervical cancer cells. Co-immunoprecipitation, subcellular fractionation, immunofluorescence, luciferase reporter assay, gain- and loss-of-function The Journal of pathology Medium 21661123
2011 Zic2 and Zic1 act as coactivators of Gli-dependent Myf5 epaxial somite-specific enhancer activity; Zic2 co-immunoprecipitates with Gli2, indicating formation of Zic2-Gli2 complexes that promote Myf5 expression. Myf5 expression in newly forming somites is delayed in Zic2 mutant embryos. Co-immunoprecipitation, reporter assays in cell lines, presomitic mesoderm explants, in situ hybridization in Zic2 mutant embryos Developmental biology Medium 21211521
2013 Zic2 determines axonal ipsilaterality in ascending dorsospinal tracts and rostromedial thalamocortical projections by inducing EphA4 expression to prevent midline crossing, and by downregulating Robo3 to ensure axons enter dorsal tracts. In vivo gain- and loss-of-function (electroporation, conditional KO), axon tracing, immunofluorescence, gene expression analysis Neuron High 24360543
2014 Zic2 controls formation and function of node cilia during gastrulation to establish cardiac situs; Zic2 mutant embryos have dysmorphic, short node cilia and depleted expression of ciliogenesis regulators Noto, Rfx3, Foxj1, and Pkd1l1 at the mid-gastrula node. Mouse genetics (Zic2 mutants), electron microscopy of node cilia, in situ hybridization for ciliogenesis transcription factors Genesis Medium 24585447
2015 Zic2 preferentially binds transcriptional enhancers genome-wide in embryonic stem cells and functions with the Mbd3/NuRD complex to regulate chromatin state and transcriptional output of differentiation-linked genes; Zic2 is required for proper ESC differentiation. ChIP-seq, genome-wide molecular studies, biochemical interaction with Mbd3/NuRD, loss-of-function in ESCs Molecular cell High 25699711
2015 ZIC2 acts upstream of OCT4 in liver cancer stem cells; ZIC2 recruits the NURF chromatin remodeling complex to the OCT4 promoter to initiate OCT4 transcriptional activation, thereby maintaining CSC self-renewal. ChIP assay, promoter reporter assay, co-immunoprecipitation, knockdown/overexpression with sphere formation and xenograft readouts The Journal of clinical investigation Medium 26426078
2015 Zic2 controls migration of three distinct forebrain neuron populations (Cajal-Retzius cells, an amygdaloid cell group from the caudal pallium, and cells from the prethalamic neuroepithelium to the ventral lateral geniculate nucleus); EphB1, a Zic2 transcriptional target, mediates at least part of Zic2-dependent migratory events. Zic2 conditional and hypomorphic mutant mice, in vivo cell tracking, in utero electroporation, immunofluorescence The Journal of neuroscience Medium 26269635
2016 ZIC2 physically interacts with SMAD2 and SMAD3 (the receptor-activated NODAL signal transducers) and together SMAD3 and ZIC2 regulate FOXA2 transcription; ZIC2 therefore acts downstream of the NODAL signal during prechordal plate development, and HPE-associated ZIC2 variants are deficient in SMAD-dependent transcription. Co-immunoprecipitation (ZIC2-SMAD2/3), luciferase reporter assays (FOXA2 promoter), Xenopus developmental assays, mutagenesis of HPE-associated ZIC2 variants Human molecular genetics High 27466203
2017 Zic2 directly binds the PAK4 promoter and transcriptionally activates PAK4 expression; PAK4 then modulates cell growth via the Raf/MEK/ERK pathway downstream of Zic2 in hepatocellular carcinoma. ChIP assay, luciferase reporter assay, knockdown/rescue experiments, pathway inhibition Cancer letters Medium 28577975
2017 ZIC2 is a substrate of the KSHV K-Rta E3 ubiquitin ligase; K-Rta directly interacts with ZIC2 and ubiquitinates it. ZIC2 localizes to immediate early and early gene cluster regions of the KSHV genome, tethers polycomb repressive complex 2 (PRC2) through physical interaction, and maintains H3K27me3 marks at the K-Rta promoter to sustain viral latency. Co-immunoprecipitation, ubiquitination assay, ChIP-seq, PRC2 interaction assay, ZIC2 depletion experiments Journal of virology Medium 28835494
2017 ZIC2 in ChIP-seq of epiblast stem cells (EpiSCs) preferentially binds enhancers that regulate transcription factor genes; ZIC2 binding at enhancers in ESCs primes these regions for later OTX2/ZIC2-dependent activation in EpiSCs, representing a shift from SOX2/POU5F1 in ESCs to ZIC2/OTX2 as major acting TFs in EpiSCs. ChIP-seq with in vivo biotinylated ZIC2, OTX2, SOX2, POU5F1, POU3F1 in EpiSCs Development (Cambridge, England) High 28455373
2018 ZIC2 directly binds a low-affinity binding site in the Nodal enhancer HBE (normally active in node precursor cells) and is required for Nodal expression at the node; loss of Zic2 prevents activation of the NODAL-dependent left-determining cascade in the lateral plate mesoderm. ChIP-seq data analysis, in vitro transcriptional assays, mutagenesis of ZIC2 binding sites, mouse Zic2 mutant gene expression analysis, 3D organ imaging Scientific reports Medium 29992973
2018 ZIC2 directly regulates Tgif1 (another HPE-causative gene) expression; Zic2-binding sites (ZBS) on the 5' flanking region of Tgif1 were identified by ChIP and in vitro DNA binding assays, and are essential for Zic2-dependent transcriptional activation. Zic2 shows higher affinity to ZBS than GLI-binding sequences. Chromatin immunoprecipitation (ChIP), in vitro DNA binding assay, luciferase reporter assay with ZBS mutations Scientific reports Medium 29391420
2018 A Zic2 missense mutation (R409P) in the zinc finger domain found in schizophrenia patients shows lowered transcription-activating capacity, impaired target DNA-binding, and impaired co-factor-binding, linking zinc finger domain integrity to Zic2 transcriptional function. Luciferase reporter assay, DNA binding assay, co-factor binding assay with mutant Zic2 protein Scientific reports Medium 22355535
2019 Zfp281 stabilizes Zic2 at enhancers and promoters in epiblast stem cells; Ehmt1 (H3K9 methyltransferase) and Zic2 act downstream of Zfp281 to drive exit from the ESC naive state and restrict reprogramming of EpiSCs to naive state. Comparative CRISPR screening in ESCs and EpiSCs, gain- and loss-of-function genetics, chromatin binding analysis The EMBO journal Medium 31782544
2020 Zic2 switches the Wnt5a-triggered alternative (non-canonical) Wnt pathway in ipsilateral retinal neurons by regulating expression of Wnt receptors and intracellular proteins; in combination with EphB1 receptor activation at the midline, βcatenin is phosphorylated to elicit axon repulsion. In vivo gain- and loss-of-function (electroporation, Zic2 conditional KO), transcriptomic analysis of Wnt receptor expression, axon tracing Science advances Medium 33188033
2020 ZIC2 directly binds the STAT3 promoter and represses STAT3 transcription; ZIC2 knockdown induces STAT3 expression and increases phosphorylated STAT3 levels, and ZIC2's tumor suppressive function in breast cancer is mediated through STAT3 regulation. ChIP-seq, RNA-seq, luciferase reporter assay, siRNA knockdown/STAT3 inhibitor rescue International journal of cancer Medium 32064600
2020 ZIC2 is identified as an essential gene for cardiac progenitor formation by genome-wide CRISPR screen; ZIC2 mutant hPSCs retain pluripotency markers but fail to differentiate into cardiomyocytes, instead switching to non-cardiac lineages, with disruption of apelin receptor-related signaling during mesoderm formation. Genome-wide CRISPR-knockout screen in hPSCs, stage-specific marker analysis (MESP1, ISL1), RNA-seq, single-cell RNA-seq Stem cells Medium 32129551
2020 SOX2 and ZIC2 combinatorially activate the Sox2 D1 enhancer in embryonic neural tube and neural crest; both TFs bind the D1 enhancer sequence (confirmed by ChIP), and their co-expression activates the enhancer in both neural tube and neural crest contexts. Chicken embryo electroporation, TF binding site mutagenesis, ChIP analysis Genes to cells Medium 31997540
2021 ZIC2 directly binds the Axin2 promoter to transcriptionally repress Axin2 expression, leading to accumulation and nuclear translocation of β-catenin; ZIC2 also physically interacts with β-catenin, providing multilevel enhancement of Wnt/β-catenin signaling in colon cancer. ChIP assay, luciferase reporter assay, co-immunoprecipitation, loss-of-function with β-catenin protein level and nuclear translocation analysis Cell death & disease Medium 34099631
2021 ZIC2 transcriptionally activates Src expression; silencing ZIC2 inactivates Src/FAK signaling and reduces anoikis resistance of NSCLC cells, placing ZIC2 upstream of Src/FAK pathway in lung cancer. ChIP assay, luciferase reporter assay, siRNA knockdown, in vitro anoikis assay, in vivo xenograft Molecular therapy oncolytics Medium 34514099
2021 ZIC2 directly binds the SNHG12 lncRNA promoter and activates SNHG12 transcription; ZIC2-driven SNHG12 upregulation activates Notch signaling to promote endometrial cancer cell proliferation and migration. ChIP assay, dual luciferase reporter assay, knockdown/overexpression with functional cell assays Molecular medicine reports Low 34278490
2023 ZIC2 positively regulates RUNX2 transcription in clear cell renal cell carcinoma; increased ZIC2 drives upregulation of Runx2 and downstream oncogenic functions including downregulation of NOLC1 and activation of AKT/mTOR signaling. ZIC2 expression is regulated by promoter hypomethylation and H3K4me3, and by positive transcriptional regulation from FOXM1. RNA-seq, ATAC-seq, ChIP-PCR, MS-PCR (methylation), luciferase reporter, loss-of-function/gain-of-function International journal of biological sciences Medium 37496990
2023 ZIC2 activates JUNB promoter activity (confirmed by ChIP-seq and ChIP-qPCR) and drives MCSF secretion from NPC cells via JUNB, inducing M2 polarization of tumor-associated macrophages; blockade of JUNB or MCSF reverses ZIC2-mediated macrophage polarization. ChIP-seq, ChIP-qPCR, luciferase assay, RNA-seq, knockdown/overexpression with macrophage polarization assay Cell death & disease Medium 37479694
2023 BMP signaling is overactivated in Zic2 (Kumba) mutant mouse embryos, causing failed dorsolateral hinge point formation and spina bifida; RhoA/actomyosin signaling is also overactivated, causing F-actin accumulation. BMP inhibitor (dorsomorphin) rescues DLHP formation, and myosin inhibitor (Blebbistatin) normalizes actomyosin accumulation, revealing a dual-pathway mechanism. Mouse mutant embryo culture with pharmacological inhibitors (dorsomorphin, Blebbistatin), immunofluorescence for actomyosin, neural tube morphology analysis Disease models & mechanisms Medium 36916392
2024 ARID1A-BAF chromatin remodeler regulates ZIC2 genomic occupancy at EMT enhancers during cranial neural crest specification; in ARID1A-haploinsufficient cells, ZIC2 is excluded from EMT enhancers and relocates to neuronal enhancers. ZIC2 binding at EMT enhancers is ARID1A-dependent. In vivo, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos elicits ectopic neural crest delamination. CSS patient iPSC-derived CNCC differentiation, ChIP-seq (ARID1A, ZIC2), ATACseq, gain-of-function in chick (electroporation), Zic2 mouse KO NCC delamination analysis American journal of human genetics High 39226899
2024 ZIC2 and ZIC3 recruit SWI/SNF to primed-specific enhancers to activate them during human primed pluripotency; loss of ZIC2/ZIC3 prevents enhancer activation similarly to SWI/SNF degradation, and also results in perturbed Polycomb activity and aberrant differentiation toward mesendoderm. Multi-omic analysis (ATAC-seq, ChIP-seq, RNA-seq) in hESC models across peri-implantation spectrum, loss-of-function of ZIC2/ZIC3, 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 281 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 198 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 106 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 84 25699711
2008 Zic2-associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation. Human molecular genetics 77 18617531
2011 Transcription factor Zic2 inhibits Wnt/β-catenin protein signaling. The Journal of biological chemistry 71 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
2013 Zic2-dependent axon midline avoidance controls the formation of major ipsilateral tracts in the CNS. Neuron 63 24360543
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
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
2010 Zic2 regulates the expression of Sert to modulate eye-specific refinement at the visual targets. The EMBO journal 58 20676059
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
2007 Zic2 and Zic3 synergistically control neurulation and segmentation of paraxial mesoderm in mouse embryo. Developmental biology 54 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 53 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
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 48 30260270
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
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
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) 46 28455373
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
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
2017 HOXA10 promotes nasopharyngeal carcinoma cell proliferation and invasion via inducing the expression of ZIC2. European review for medical and pharmacological sciences 42 28338202
2001 Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. Human genetics 42 11479728
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 34 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
2016 Zic2 mutation causes holoprosencephaly via disruption of NODAL signalling. Human molecular genetics 30 27466203
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
2010 Expression of the zic1, zic2, zic3, and zic4 genes in early chick embryos. BMC research notes 29 20553611
2022 ZIC2 promotes colorectal cancer growth and metastasis through the TGF-β signaling pathway. Experimental cell research 28 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 28 26269635
2019 Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2. The EMBO journal 27 31782544
2002 Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene. American journal of medical genetics 27 11857562
2021 Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung cancer cells by inhibiting Src/FAK signaling. Molecular therapy oncolytics 25 34514099
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
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) 24 32129551
2020 A Zic2-regulated switch in a noncanonical Wnt/βcatenin pathway is essential for the formation of bilateral circuits. Science advances 24 33188033
2008 Zic2 is expressed in pluripotent cells in the blastocyst and adult brain expression overlaps with makers of neurogenesis. Gene expression patterns : GEP 24 18755297
2021 De novo ZIC2 frameshift variant associated with frontonasal dysplasia in a Limousin calf. BMC genomics 23 33388042
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
2023 FOXM1-regulated ZIC2 promotes the malignant phenotype of renal clear cell carcinoma by activating UBE2C/mTOR signaling pathway. International journal of biological sciences 20 37496990
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
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 19 31997540
2017 Zebrafish zic2 controls formation of periocular neural crest and choroid fissure morphogenesis. Developmental biology 19 28689736
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
2023 ZIC2 induces pro-tumor macrophage polarization in nasopharyngeal carcinoma by activating the JUNB/MCSF axis. Cell death & disease 16 37479694
2018 ZIC2 in Holoprosencephaly. Advances in experimental medicine and biology 16 29442327
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 14 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
2024 ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial-to-mesenchymal transition in cranial neural crest specification. American journal of human genetics 12 39226899
2024 ZIC2 and ZIC3 promote SWI/SNF recruitment to safeguard progression towards human primed pluripotency. Nature communications 11 39358345
2007 Functional role of Zic2 phosphorylation in transcriptional regulation. FEBS letters 11 18068128
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
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
2023 Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse. Disease models & mechanisms 5 36916392
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 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

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