Affinage

ZIC1

Zinc finger protein ZIC 1 · UniProt Q15915

Length
447 aa
Mass
48.3 kDa
Annotated
2026-06-11
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZIC1 is a nuclear zinc finger transcription factor that governs the balance between neural progenitor expansion and differentiation and that specifies multiple ectodermal and mesodermal cell fates during development (PMID:9435279, PMID:9412507, PMID:11944941). Through its zinc finger domains it binds DNA sequences nearly identical to the GLI consensus, though with lower affinity than GLI, and activates or represses transcription from diverse promoters and enhancers in a cell-type-dependent manner (PMID:7931345, PMID:11053430); genome-wide it occupies enhancers bearing Zic consensus motifs (CTGCTG-core and GC-stretch types) (PMID:25849986, PMID:29442331). ZIC1 physically associates with GLI proteins through their zinc fingers and reciprocally modulates GLI transcriptional activity and nuclear translocation (PMID:11238441), a partnership it uses to potentiate Gli-dependent transactivation of the Myf5 epaxial somite enhancer during myogenesis (PMID:21211521). In neural development ZIC1 maintains progenitors in an undifferentiated, proliferative state — inhibiting neuronal differentiation in the dorsal spinal cord by upregulating Notch1 and repressing the proneural enhancer of Math1 (PMID:11944941, PMID:12642498), sustaining medial forebrain precursors (PMID:17507568), and driving Shh-dependent granule cell progenitor proliferation in the cerebellum (PMID:9412507, PMID:21307096). At the neural plate border ZIC1 acts combinatorially with Pax3: together they are necessary and sufficient to commit cells to neural crest by directly activating Snail1/2, Foxd3, Twist1, Sox9, and Tfap2b and modulating Wnt and retinoic acid regulators, whereas ZIC1 alone promotes preplacodal/cranial placode fate, in part non-cell-autonomously through induction of RA-synthesizing enzymes (PMID:15843410, PMID:17409353, PMID:24360906, PMID:26101153). ZIC1 also functions upstream of Wnt ligands in neural patterning and modulates Wnt output by binding β-catenin/TCF4 to disrupt the complex and downregulate Wnt targets (PMID:16892174, PMID:31909528). Its activity is controlled by importin/CRM1-dependent nucleocytoplasmic shuttling and proteasomal turnover, and by negative regulators such as I-mfa, which blocks its nuclear import (PMID:15207726, PMID:29442331). Gain-of-function mutations in the final exon of ZIC1 escape nonsense-mediated decay and produce enhanced transcriptional activity, causing coronal craniosynostosis (PMID:26340333).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 Medium

    Established the founding biochemical identity of ZIC1 — that it is a nuclear zinc finger protein capable of binding the GLI recognition sequence, linking it to the Hedgehog/GLI regulatory machinery.

    Evidence Recombinant ZIC1 DNA-binding assay and immunohistochemistry in cerebellar granule cells

    PMID:7931345

    Open questions at the time
    • In vitro binding did not establish endogenous target genes
    • No functional consequence of DNA binding shown
  2. 1998 High

    Defined ZIC1's developmental role by showing it acts in the neural induction hierarchy downstream of neural inducers and upstream of proneural genes, and is genetically required for cerebellar granule progenitor proliferation.

    Evidence Xenopus animal cap and embryo gain-of-function; targeted Zic1 knockout mouse with BrdU labeling

    PMID:9412507 PMID:9435279

    Open questions at the time
    • Direct transcriptional targets in proliferation not identified
    • Mechanism coupling Zic1 to the cell cycle unresolved
  3. 2000 High

    Resolved the DNA-binding specificity of Zic proteins relative to GLI and showed they regulate transcription less dependently on the GLI site, while identifying APOE as a bona fide direct target promoter.

    Evidence EMSA-based target selection with mutagenesis; reporter assays; yeast one-hybrid and endogenous APOE measurement

    PMID:11038359 PMID:11053430

    Open questions at the time
    • Determinants of activation vs repression at a given promoter unclear
    • Genome-wide occupancy not yet established
  4. 2001 High

    Demonstrated a physical and functional ZIC–GLI partnership, explaining how ZIC modulates Hedgehog output through direct protein interaction and cross-regulation of nuclear localization.

    Evidence Co-immunoprecipitation, nuclear translocation imaging, and reporter assays

    PMID:11238441

    Open questions at the time
    • Stoichiometry and which interaction dominates in a given tissue not defined
    • Structural basis of the zinc-finger interaction not solved
  5. 2002 High

    Established that ZIC1 promotes progenitor expansion by inhibiting neuronal differentiation, implicating Notch1 upregulation as a downstream effector and showing Zic1/Zic2 cooperativity via cell-cycle regulators.

    Evidence Chick electroporation, transgenic and knockout mice, compound mutant genetics with cyclin D1/p27/p16 readouts

    PMID:11756505 PMID:11944941

    Open questions at the time
    • Whether Notch1 is a direct Zic1 target not shown
    • Direct cell-cycle gene targets not mapped
  6. 2003 High

    Provided direct enhancer-level mechanism for the anti-differentiation role by showing ZIC1 binds and represses the Math1 enhancer, blocking proneural autoregulation, and identified teneurin-2 ICD as a negative modulator of ZIC1 activity.

    Evidence Math1 enhancer reporter with mutational analysis in chick neural tube; reporter inhibition assays for teneurin-2 ICD

    PMID:12642498 PMID:12783990

    Open questions at the time
    • Cofactors mediating repression at Math1 unknown
    • Physiological relevance of teneurin-2 ICD regulation in vivo untested
  7. 2004 Medium

    Identified I-mfa as a regulator that controls ZIC activity by binding the N-terminal domain and blocking nuclear import, introducing subcellular trafficking as a control point.

    Evidence Co-IP, nuclear localization imaging, reporter assays, and domain mapping

    PMID:15207726

    Open questions at the time
    • In vivo significance of I-mfa regulation not demonstrated
    • Single lab without reciprocal validation
  8. 2007 High

    Defined the combinatorial logic at the neural plate border, showing distinct and shared fate outcomes of Zic1 and Pax3 (preplacodal alone, neural crest together) and the Wnt-dependence of neural crest induction.

    Evidence Xenopus reciprocal gain- and loss-of-function with fate-shifting and Wnt inhibitor experiments

    PMID:15843410 PMID:17409353

    Open questions at the time
    • Direct transcriptional targets driving each fate not yet identified at this stage
    • Mechanism of Pax3-Zic1 cooperativity at chromatin unresolved
  9. 2009 High

    Placed ZIC1 upstream of and within multiple signaling pathways during patterning, regulating Wnt ligand expression, Nodal/Hedgehog maintenance, and retinoic acid levels via cyp26a1, and showed Zic1 itself is a direct BMP-inhibition target.

    Evidence Xenopus and zebrafish knockdown/gain-of-function with pathway epistasis; cycloheximide block

    PMID:16892174 PMID:19528322 PMID:19805078

    Open questions at the time
    • Direct vs indirect regulation of each pathway gene not fully separated
    • Cross-pathway integration mechanism unclear
  10. 2011 High

    Extended ZIC1's GLI partnership into myogenesis, showing Zic potentiates Gli-dependent transactivation of the Myf5 epaxial enhancer with Zic2-Gli2 physical interaction, and dissected Shh-dependent vs -independent cerebellar functions.

    Evidence Reporter transactivation, co-IP (Zic2-Gli2), explant culture, and Zic1/Zic4-Shh compound mouse genetics

    PMID:21211521 PMID:21307096

    Open questions at the time
    • ZIC1-specific (vs ZIC2) direct binding to the Myf5 enhancer not separately resolved
    • Mechanism of the Shh-independent foliation role unknown
  11. 2013 High

    Identified the direct neural crest target gene network of Pax3/Zic1 (Snail1/2, Foxd3, Twist1, Sox9, Tfap2b, plus Wnt/RA regulators) and showed coactivation is sufficient to drive full neural crest commitment and differentiation.

    Evidence Transcriptome profiling with cycloheximide block, inducible fusion proteins, in situ validation, and transplantation assays in Xenopus and chick

    PMID:23509273 PMID:24036067 PMID:24360906 PMID:24360908

    Open questions at the time
    • Direct ZIC1 chromatin occupancy at these loci not all confirmed by ChIP
    • Division of labor between Pax3 and Zic1 at individual targets unclear
  12. 2015 High

    Mapped ZIC1's genome-wide enhancer occupancy and maturation-gene program in granule neurons, defined a non-cell-autonomous RA-based mechanism for placode induction, placed Zic1 in the Brn2 axis, and linked final-exon gain-of-function mutations to coronal craniosynostosis.

    Evidence Zic1/2 ChIP-seq with CRISPR activation and knockdown; RALDH2/LPGDS morpholino assays; Brn2 ChIP-seq; human genetics with NMD-escape and Xenopus reporter assays

    PMID:25849986 PMID:25991548 PMID:26101153 PMID:26340333

    Open questions at the time
    • Direct target genes mediating the craniosynostosis phenotype not identified
    • How enhanced transcriptional activity translates to suture pathology unknown
  13. 2017 Medium

    Revealed an evolutionarily conserved role for Zic1/Zic2 in suppressing dopaminergic fate and promoting GABAergic neuron generation in postnatal forebrain stem cells.

    Evidence Mouse postnatal lineage tracing with gain/loss-of-function and C. elegans genetics

    PMID:28972122

    Open questions at the time
    • Direct repressed targets in the dopaminergic program not defined
    • ZIC1-specific contribution vs ZIC2 not separated
  14. 2020 Medium

    Defined a tumor-suppressive mechanism in which ZIC1 binds β-catenin/TCF4 to disrupt the complex and downregulate Wnt targets, and earlier work showed ZIC1 transcriptionally represses oncogenic miRNAs in mesothelioma.

    Evidence Co-IP, LEF reporter, invasion assays and xenograft; ChIP-PCR at miR-23a/27a loci with functional assays

    PMID:24457242 PMID:31909528

    Open questions at the time
    • Generality of the β-catenin/TCF4 mechanism across tissues untested
    • Single-lab co-IP without orthogonal interaction validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZIC1's context-dependent switch between activation and repression, and between progenitor maintenance and fate specification, is encoded at the level of cofactor selection and chromatin state remains unresolved.
  • No structural model of ZIC1 on its CTGCTG-core vs GC-stretch sites
  • Rules governing partner choice (GLI vs Pax3 vs β-catenin/TCF4) not established
  • Mechanism by which craniosynostosis mutations alter target selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0140110 transcription regulator activity 6 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
CTNNB1GLI1GLI2GLI3PAX3SMAD2TCF4TENM2

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 ZIC1 (zic) protein contains zinc finger domains that bind the GLI-binding sequence in vitro, and localizes to the nucleus of cerebellar granule cells and their precursors. Bacterially expressed recombinant ZIC1 protein DNA-binding assay; immunohistochemical nuclear localization Journal of neurochemistry Medium 7931345
1998 Xenopus Zic-related-1 (ortholog of ZIC1) activates the proneural gene Xngnr-1 and initiates neural and neuronal differentiation in isolated animal caps and in vivo, acting downstream of neural inducers (Chordin) and upstream of proneural genes. mRNA microinjection in Xenopus animal cap and whole-embryo assay; in situ hybridization for marker genes Development (Cambridge, England) High 9435279
1998 Mouse Zic1 is required for normal cerebellar folial patterning and granule cell progenitor proliferation; Zic1-deficient mice show reduced BrdU-labeling in the external germinal layer beginning at E14, leading to cerebellar hypoplasia and missing anterior lobe lobule. Targeted Zic1 knockout mouse; BrdU labeling; histological analysis The Journal of neuroscience High 9412507
2000 ZIC1, ZIC2, and ZIC3 proteins bind a DNA sequence nearly identical to the GLI binding sequence (established by EMSA-based target selection and mutational analysis), but with lower affinity than GLI. Zic proteins activate transcription from multiple promoters in a manner less dependent on the GLI binding sequence than GLI1, and can enhance or suppress GLI-mediated transactivation in a cell-type-dependent manner. Electrophoretic mobility shift assay (EMSA)-based target selection; mutational analysis; reporter (luciferase) cotransfection assays The Journal of biological chemistry High 11053430
2000 ZIC1 and ZIC2 bind specific sequences in the apolipoprotein E (APOE) gene promoter (at -136/-125, -65/-54, and -185/-174 regions) and transactivate APOE promoter-driven reporter constructs, also increasing endogenous APOE production in U87 glioblastoma cells. Yeast one-hybrid screen; EMSA with mutational analysis; reporter cotransfection; endogenous gene expression measurement The Journal of biological chemistry High 11038359
2001 ZIC and GLI proteins physically interact through their zinc finger domains; coexpressed ZIC proteins translocate GLI proteins to the cell nucleus, and both proteins regulate each other's transcriptional activity. Co-immunoprecipitation; nuclear translocation imaging; transcriptional reporter assays The Journal of biological chemistry High 11238441
2002 Zic1 promotes expansion of dorsal neural progenitors by inhibiting neuronal differentiation; misexpression of Zic1 on the ventral side of chick spinal cord inhibits neuronal differentiation, transgenic Zic1 overexpression causes hypercellularity in the dorsal spinal cord, and Zic1-deficient mice show reduced dorsal spinal cord cell numbers. Notch1 is upregulated in Zic1-overexpressing spinal cords, suggesting Notch-mediated inhibition of neuronal differentiation acts downstream of Zic1. Chick in ovo electroporation; transgenic mouse overexpression; Zic1 knockout mouse; cell counting; molecular marker analysis Developmental biology High 11944941
2002 Zic1 and Zic2 cooperatively regulate cerebellar development by controlling neuronal differentiation; compound Zic1+/-;Zic2+/kd mice show cerebellar folial abnormalities with reduced cyclin D1 expression and increased p27 and p16, preceding a reduction in EGL cell proliferation similar to Zic1-/- mice. Compound mutant mouse genetics; immunohistochemistry; molecular marker analysis The Journal of neuroscience High 11756505
2003 Zic1 binds a conserved site within the Math1 enhancer and represses Math1 expression; Zic1 blocks Math1 autoregulation and inhibits neuronal differentiation in the chick neural tube when overexpressed. Chick neural tube electroporation; Math1 enhancer-lacZ reporter assays; in situ hybridization for endogenous Cath1; enhancer mutational analysis Development (Cambridge, England) High 12642498
2003 The intracellular domain of teneurin-2, when released and translocated to the nucleus, inhibits Zic1-mediated transcriptional activation from the apolipoprotein E promoter; this inhibition can be stimulated by homophilic teneurin-2 interaction. Reporter gene (luciferase) cotransfection; nuclear colocalization of teneurin-2 intracellular domain with PML bodies; proteasome inhibitor stabilization experiment Journal of cell science Medium 12783990
2004 I-mfa (inhibitor of MyoD family) physically interacts with the amino-terminal domain of Zic proteins (Zic1–3) and inhibits their nuclear import, thereby suppressing Zic-mediated transcriptional activation in cultured cells. Co-immunoprecipitation; nuclear localization imaging; transcriptional reporter assays; domain mapping Biochemical and biophysical research communications Medium 15207726
2005 Cooperative function of Pax3 and Zic1 is necessary and sufficient to initiate neural crest determination in Xenopus ectoderm; co-misexpression of both factors induces ectopic neural crest in ventral ectoderm, and this induction requires Wnt signaling. Loss-of-function of either factor alone fails to initiate neural crest fate. Xenopus mRNA microinjection (gain-of-function); morpholino knockdown (loss-of-function); animal cap assay; in situ hybridization for neural crest markers; Wnt pathway inhibitor treatment Development (Cambridge, England) High 15843410
2006 Xenopus Zic1 is an upstream activator of Wnt signaling; it induces expression of wnt1, wnt4, and wnt8b, and activation of en-2 expression by Zic1 requires an active Wnt pathway. This places Zic1 upstream of multiple Wnt genes in neural patterning. Xenopus mRNA injection; RT-PCR for Wnt target genes; pharmacological Wnt pathway inhibitor experiments; in situ hybridization The International journal of developmental biology Medium 16892174
2007 Pax3 and Zic1 determine distinct cell fates at the neural plate border: Zic1 alone is necessary and sufficient to promote preplacodal ectoderm fate, Pax3 alone promotes hatching gland fate, and their combined activity is essential to specify neural crest. Manipulating levels of each factor can shift fates among these lineages. Xenopus gain-of-function (mRNA injection) and knockdown (morpholino); animal explant assays; in situ hybridization for lineage markers Molecular biology of the cell High 17409353
2007 Zic1 and Zic3 are required for medial forebrain development by maintaining neural precursor cells in an undifferentiated state; compound Zic1/Zic3 mutant mice show increased cell cycle exit rate in the septa, causing hypoplasia of hippocampus, septum, and olfactory bulb. Compound Zic1/Zic3 mutant mouse genetics; cell cycle analysis; Zic3 misexpression in cerebral cortex; histological and molecular marker analysis The Journal of neuroscience High 17507568
2009 Zebrafish Zic1 controls midline formation and forebrain patterning by maintaining Nodal and Hedgehog signaling in the anterior ventral diencephalon; Zic1 knockdown also reduces expression of the RA-degrading enzyme cyp26a1, leading to increased RA levels, ventralization of optic vesicle, and downregulation of dorsal BMP signaling. Zebrafish morpholino knockdown; in situ hybridization for pathway markers; epistasis with Nodal, Hedgehog, and RA pathway components Genes & development High 19528322
2009 Zic1 can be activated by BMP inhibition independently of translation (i.e., as a direct transcriptional target), while Zic1 and Zic3 are jointly required for definitive neural fate acquisition in both ectopic and endogenous neural induction contexts in Xenopus. Xenopus dominant-negative R-Smad injection; cycloheximide protein synthesis block; morpholino knockdown of Zic1 and Zic3; animal cap assay Proceedings of the National Academy of Sciences of the United States of America Medium 19805078
2010 ZIC1 in osteocytes localizes to both cytosol and nucleus; oscillatory fluid flow causes nuclear translocation of ZIC1, and ZIC1 gene silencing abolishes shear stress-induced TCF/LEF transcriptional activity, linking ZIC1 to mechanotransduction and Wnt signaling in osteocytes. Immunolocalization in osteocyte and osteoblast cell lines; fluid flow apparatus; shRNA knockdown; TCF/LEF luciferase reporter assay FASEB journal Medium 20354137
2011 Zic1 and Zic4 have both Shh-dependent and Shh-independent roles in cerebellar development: they promote granule cell progenitor proliferation via Shh signaling (Ptch1, Gli1, and Mycn are downregulated in Zic1/4 mutants; Shh dose reduction on Zic1+/-;Zic4+/- background phenocopies full mutant), while anterior vermis foliation patterning is Shh-independent. Zic1/Zic4 compound mutant mice; Shh compound genetic interaction; conditional Smo and Gli2 knockout; in situ hybridization and immunohistochemistry for pathway targets Development (Cambridge, England) High 21307096
2011 Zic1 and Zic2 regulate somite myogenesis by potentiating Gli-dependent transactivation of the Myf5 epaxial somite enhancer; Zic2 co-immunoprecipitates with Gli2, and Zic1 activates endogenous Myf5 expression in 10T1/2 cells and presomitic mesoderm explants. Myf5 activation in newly forming somites is delayed in Zic2 mutant embryos until Zic1 is activated. Reporter (luciferase) transactivation assays; co-immunoprecipitation (Zic2-Gli2); Myf5 loss-of-function in Zic2 mutant and Shh mutant mice; presomitic mesoderm explant culture Developmental biology High 21211521
2013 Pax3 and Zic1 are direct upstream activators of neural crest specifiers Snail1/2, Foxd3, Twist1, and Tfap2b, and modulate Wnt (via Axin2) and retinoic acid (via Cyp26c1) pathway regulators as direct targets. Identified by combining transcriptome profiling with protein translation blockade. Xenopus microdissection transcriptome analysis; microarray with Pax3/Zic1 gain-of-function plus cycloheximide block to identify direct targets; in situ hybridization validation Developmental biology High 24360906
2013 Pax3 and Zic1 coactivation is sufficient to trigger full neural crest commitment including migration and differentiation of multiple neural crest derivatives in vitro and in vivo in Xenopus and chicken embryos; induced cells migrate to and integrate into normal craniofacial territories after transplantation. Xenopus and chick gain-of-function mRNA injection; ectopic lineage induction assays; in vitro minimal culture differentiation; transplantation into host embryos Proceedings of the National Academy of Sciences of the United States of America High 23509273
2015 Zic1 controls cranial placode progenitor fate non-cell autonomously by inducing expression of RALDH2 and LPGDS, which regulate the synthesis and transport of retinoic acid (RA), leading to localized RA production that activates placode developmental programmes in neighboring cells. Xenopus Zic1 gain-of-function; transcriptome screen for Zic1 targets; morpholino knockdown of RALDH2 and LPGDS; RA signaling reporter assays Nature communications High 26101153
2015 Gain-of-function mutations in the final exon of ZIC1 (four nonsense and one missense) escape nonsense-mediated decay, produce altered/enhanced transcriptional activation of the target gene engrailed-2 in a Xenopus embryo assay, and are associated with coronal craniosynostosis. Human genetics (five families); NMD escape confirmed in patient cell line; Xenopus embryo engrailed-2 reporter assay for functional characterization of mutant alleles American journal of human genetics High 26340333
2015 Zic1 and Zic2 are required for mature neuronal gene expression in cerebellar granule neurons; Zic1/2 ChIP-seq shows binding to enhancers enriched for Zic motifs, and Zic1/2 knockdown disrupts coordinated maturation gene expression. DNase-seq; RNA-seq; H3K27ac ChIP-seq; Zic1/2 ChIP-seq; reporter assays; CRISPR activation; shRNA knockdown Nature neuroscience High 25849986
2015 Brn2 directly activates Zic1 transcription during retinoic-acid-induced neuronal differentiation of mouse ESCs; shRNA-mediated knockdown of Zic1 prevents ESC differentiation into neuronal precursors, establishing a hierarchical Brn2-Zic1 axis for neural fate specification. Brn2 ChIP-seq; RNA-seq after Brn2 silencing; shRNA knockdown of Zic1; neuronal differentiation assay from ESCs Journal of cell science Medium 25991548
2017 Zic1 and Zic2 suppress dopaminergic fate and promote calretinin-positive GABAergic neuron generation in the postnatal dorsal forebrain neural stem cell lineage; this dopaminergic repressor function is conserved in C. elegans. Mouse postnatal neural stem cell lineage tracing; transcriptomic analysis; gain-of-function and loss-of-function of Zic1/Zic2; C. elegans genetic analysis The Journal of neuroscience Medium 28972122
2018 Zic proteins (including ZIC1) undergo importin- and CRM1-based nucleocytoplasmic shuttling; their degradation is mediated by the ubiquitin proteasome system. Zic proteins bind two types of DNA sequences (CTGCTG-core-type and GC-stretch-type), with CTGCTG-core-type enriched at enhancers by ChIP-seq. ZIC1 physically interacts with Gli1-3, Tcf1/Tcf4, Smad2/3, Oct4, Pax3, Cdx, SRF, chromatin-remodeling complexes NuRD and NURF, and nuclear enzymes DNA-PK, PARP1, and RNA helicase A. Review integrating ChIP-seq data, co-immunoprecipitation, nuclear transport inhibitor studies, proteasome inhibitor studies from multiple primary studies Advances in experimental medicine and biology Medium 29442331
2020 ZIC1 physically interacts with β-catenin/TCF4, disrupts their complex formation (without affecting β-catenin nuclear localization), and thereby downregulates Wnt target genes (c-Myc, Cyclin D1), suppressing gastric cancer cell invasion and EMT. Co-immunoprecipitation of ZIC1 with β-catenin and TCF4; reporter assay for LEF transcriptional activity; in vitro invasion/adhesion assays; in vivo xenograft metastasis model FASEB journal Medium 31909528
2013 ZIC1 reexpression in malignant pleural mesothelioma cells inhibits proliferation and invasion; ZIC1 knockdown promotes growth. ZIC1 transcriptionally downregulates miR-23a and miR-27a, confirmed by chromatin immunoprecipitation, and inhibition of these miRNAs reduces colony formation. ZIC1 reexpression (lentiviral) and knockdown; ChIP-PCR confirming ZIC1 binding at miR-23a/27a loci; miRNA inhibitor functional assay; proliferation/invasion assays Journal of thoracic oncology Medium 24457242
2016 Geminin and Zic1 co-associate with chromatin at a shared subset of neurodevelopmental gene loci during neural fate acquisition, and cooperatively activate expression of targets encoding regulators of neurogenesis and neural plate patterning. Zic1-bound peaks are enriched for both Zic1 consensus motifs and Sox3 motifs, suggesting co-regulatory activity. Genome-wide chromatin association by ChIP-seq (Geminin and Zic1); histone acetylation ChIP-seq; cooperative target gene activation assays; motif analysis Scientific reports Medium 27881878
2013 Pax3 and Zic1 directly regulate specific neural crest specifiers (snail2, foxd3, gbx2, twist, sox8, sox9) as downstream targets, identified by hormone-inducible fusion protein combined with DNA microarray in Xenopus animal cap assay. Hormone-inducible Pax3/Zic1 fusion proteins; Xenopus animal cap microarray; qRT-PCR validation; morpholino knockdown of selected targets Developmental biology Medium 24360908
2013 Pax3 synergizes with Zic1 and Gli2 to transactivate the Myf5 epaxial somite (ES) enhancer; overexpression of Zic1 and Pax3 in 10T1/2 cells enriches both factors at the endogenous Myf5 locus (by ChIP) and induces Myf5 expression. Synergy depends on conserved protein domains and a homeodomain motif in the Myf5 promoter and the Gli motif in the ES enhancer. Reporter (luciferase) synergy assays; ChIP at the endogenous Myf5 locus; domain mutational analysis; 10T1/2 cell Myf5 induction assay Developmental biology Medium 24036067

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Xenopus Zic-related-1 and Sox-2, two factors induced by chordin, have distinct activities in the initiation of neural induction. Development (Cambridge, England) 392 9435279
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
2004 The role of Zic genes in neural development. Molecular and cellular neurosciences 225 15207846
1994 A novel zinc finger protein, zic, is involved in neurogenesis, especially in the cell lineage of cerebellar granule cells. Journal of neurochemistry 207 7931345
1998 Gli/Zic factors pattern the neural plate by defining domains of cell differentiation. Nature 192 9634234
2005 Neural crest determination by co-activation of Pax3 and Zic1 genes in Xenopus ectoderm. Development (Cambridge, England) 175 15843410
1996 The mouse zic gene family. Homologues of the Drosophila pair-rule gene odd-paired. The Journal of biological chemistry 171 8557628
1998 Mouse Zic1 is involved in cerebellar development. The Journal of neuroscience : the official journal of the Society for Neuroscience 159 9412507
2001 Physical and functional interactions between Zic and Gli proteins. The Journal of biological chemistry 158 11238441
2000 Molecular properties of Zic proteins as transcriptional regulators and their relationship to GLI proteins. The Journal of biological chemistry 152 11053430
2007 Evaluation and optimization of ZIC-HILIC-RP as an alternative MudPIT strategy. Journal of proteome research 146 17256977
2007 The activity of Pax3 and Zic1 regulates three distinct cell fates at the neural plate border. Molecular biology of the cell 146 17409353
1998 Xenopus Zic family and its role in neural and neural crest development. Mechanisms of development 145 9739105
2015 Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum. Nature neuroscience 132 25849986
2007 Emerging roles for zic genes in early development. Developmental dynamics : an official publication of the American Association of Anatomists 126 17330889
1996 Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer research 124 8542595
2005 The ZIC gene family in development and disease. Clinical genetics 120 15733262
2002 Zic1 promotes the expansion of dorsal neural progenitors in spinal cord by inhibiting neuronal differentiation. Developmental biology 118 11944941
2002 Zic2 controls cerebellar development in cooperation with Zic1. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 11756505
2011 Zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC and ZIC-cHILIC) provide high resolution separation and increase sensitivity in proteome analysis. Analytical chemistry 106 21443167
2009 BMP inhibition initiates neural induction via FGF signaling and Zic genes. Proceedings of the National Academy of Sciences of the United States of America 105 19805078
2013 Pax3 and Zic1 trigger the early neural crest gene regulatory network by the direct activation of multiple key neural crest specifiers. Developmental biology 103 24360906
2002 Multiple functions of a Zic-like gene in the differentiation of notochord, central nervous system and muscle in Ciona savignyi embryos. Development (Cambridge, England) 102 12015299
2007 Zic1 and Zic3 regulate medial forebrain development through expansion of neuronal progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 96 17507568
2013 Pax3 and Zic1 drive induction and differentiation of multipotent, migratory, and functional neural crest in Xenopus embryos. Proceedings of the National Academy of Sciences of the United States of America 94 23509273
2011 Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis. Development (Cambridge, England) 92 21307096
2000 A novel member of the Xenopus Zic family, Zic5, mediates neural crest development. Mechanisms of development 88 11091076
2012 BMP, Wnt and FGF signals are integrated through evolutionarily conserved enhancers to achieve robust expression of Pax3 and Zic genes at the zebrafish neural plate border. Development (Cambridge, England) 83 23034628
2003 The intracellular domain of teneurin-2 has a nuclear function and represses zic-1-mediated transcription. Journal of cell science 82 12783990
2014 Stem cell-dependent formation of a functional anterior regeneration pole in planarians requires Zic and Forkhead transcription factors. Developmental biology 81 24704339
2013 The ZIC gene family encodes multi-functional proteins essential for patterning and morphogenesis. Cellular and molecular life sciences : CMLS 81 23443491
2003 Zic1 represses Math1 expression via interactions with the Math1 enhancer and modulation of Math1 autoregulation. Development (Cambridge, England) 79 12642498
2014 zic-1 Expression in Planarian neoblasts after injury controls anterior pole regeneration. PLoS genetics 70 24992682
2011 Elucidation of glycoprotein structures by unspecific proteolysis and direct nanoESI mass spectrometric analysis of ZIC-HILIC-enriched glycopeptides. Journal of proteome research 69 21443200
2003 A genomewide survey of developmentally relevant genes in Ciona intestinalis. IV. Genes for HMG transcriptional regulators, bZip and GATA/Gli/Zic/Snail. Development genes and evolution 68 12743819
2006 A wide-range phylogenetic analysis of Zic proteins: implications for correlations between protein structure conservation and body plan complexity. Genomics 65 16574373
2008 Zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type II lissencephaly. The Journal of neuroscience : the official journal of the Society for Neuroscience 63 18448648
1996 Identification and characterization of Zic4, a new member of the mouse Zic gene family. Gene 61 8682319
2007 Zic1 and Zic4 regulate zebrafish roof plate specification and hindbrain ventricle morphogenesis. Developmental biology 57 18191121
2015 Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability. American journal of human genetics 55 26340333
2003 Protochordate Zic genes define primitive somite compartments and highlight molecular changes underlying neural crest evolution. Evolution & development 55 12622730
2011 ZIC1 is downregulated through promoter hypermethylation, and functions as a tumor suppressor gene in colorectal cancer. PloS one 54 21347233
2006 The zic1 gene is an activator of Wnt signaling. The International journal of developmental biology 52 16892174
2004 Hyzic, the Hydra homolog of the zic/odd-paired gene, is involved in the early specification of the sensory nematocytes. Development (Cambridge, England) 51 14681184
2002 HrzicN, a new Zic family gene of ascidians, plays essential roles in the neural tube and notochord development. Development (Cambridge, England) 51 12421701
1999 Zebrafish zic1 expression in brain and somites is affected by BMP and hedgehog signalling. Mechanisms of development 51 10415355
2000 Transcription factors Zic1 and Zic2 bind and transactivate the apolipoprotein E gene promoter. The Journal of biological chemistry 50 11038359
2013 Identification of Pax3 and Zic1 targets in the developing neural crest. Developmental biology 48 24360908
2009 ZIC1 is downregulated through promoter hypermethylation in gastric cancer. Biochemical and biophysical research communications 47 19135984
2021 CircMTO1 suppresses hepatocellular carcinoma progression via the miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling pathway and epithelial-to-mesenchymal transition. Cell death & disease 46 34930906
2014 ZIC1 is a putative tumor suppressor in thyroid cancer by modulating major signaling pathways and transcription factor FOXO3a. The Journal of clinical endocrinology and metabolism 46 24684457
2012 Zinc fingers of the cerebellum (Zic): transcription factors and co-factors. The international journal of biochemistry & cell biology 46 22964024
2010 Expression of ZIC family genes in meningiomas and other brain tumors. BMC cancer 46 20199689
2010 Enhanced glyco-profiling by specific glycopeptide enrichment and complementary monolithic nano-LC (ZIC-HILIC/RP18e)/ESI-MS analysis. Journal of separation science 46 20222078
2006 Overlapping expression of FoxA and Zic confers responsiveness to FGF signaling to specify notochord in ascidian embryos. Developmental biology 46 16950241
2012 ZIC1 modulates cell-cycle distributions and cell migration through regulation of sonic hedgehog, PI(3)K and MAPK signaling pathways in gastric cancer. BMC cancer 45 22799764
2004 Myogenic repressor I-mfa interferes with the function of Zic family proteins. Biochemical and biophysical research communications 44 15207726
2009 Zic-associated holoprosencephaly: zebrafish Zic1 controls midline formation and forebrain patterning by regulating Nodal, Hedgehog, and retinoic acid signaling. Genes & development 43 19528322
2001 Behavioral abnormalities of Zic1 and Zic2 mutant mice: implications as models for human neurological disorders. Behavior genetics 43 11699604
2010 ZIC1 overexpression is oncogenic in liposarcoma. Cancer research 42 20713527
2008 ZIC antibodies in paraneoplastic cerebellar degeneration and small cell lung cancer. Journal of neuroimmunology 41 18639938
2020 Zygotic pioneer factor activity of Odd-paired/Zic is necessary for late function of the Drosophila segmentation network. eLife 40 32347792
2010 Expression and phylogenetic analysis of the zic gene family in the evolution and development of metazoans. EvoDevo 40 21054859
2015 Atypical Transcriptional Activation by TCF via a Zic Transcription Factor in C. elegans Neuronal Precursors. Developmental cell 38 26073017
2007 Direct activation by Ets and Zic is required for initial expression of the Brachyury gene in the ascidian notochord. Developmental biology 37 17459364
2017 Ultrathin Au nanowires assisted magnetic graphene-silica ZIC-HILIC composites for highly specific enrichment of N-linked glycopeptides. Analytica chimica acta 36 28433058
2010 Zic1 transcription factor in bone: neural developmental protein regulates mechanotransduction in osteocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 20354137
2021 Performance of DNA methylation analysis of ASCL1, LHX8, ST6GALNAC5, GHSR, ZIC1 and SST for the triage of HPV-positive women: Results from a Dutch primary HPV-based screening cohort. International journal of cancer 32 34558659
2017 Combined Detection of Plasma ZIC1, HOXD10 and RUNX3 Methylation is a Promising Strategy for Early Detection of Gastric Cancer and Precancerous Lesions. Journal of Cancer 32 28529617
2012 The medaka zic1/zic4 mutant provides molecular insights into teleost caudal fin evolution. Current biology : CB 32 22386310
2018 ZIC1 Function in Normal Cerebellar Development and Human Developmental Pathology. Advances in experimental medicine and biology 31 29442326
2021 ZIC-cHILIC-Based StageTip for Simultaneous Glycopeptide Enrichment and Fractionation toward Large-Scale N-Sialoglycoproteomics. Analytical chemistry 30 34780171
2020 Zic1 suppresses gastric cancer metastasis by regulating Wnt/β-catenin signaling and epithelial-mesenchymal transition. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 31909528
2015 Zic1 controls placode progenitor formation non-cell autonomously by regulating retinoic acid production and transport. Nature communications 30 26101153
2011 A role for Zic1 and Zic2 in Myf5 regulation and somite myogenesis. Developmental biology 30 21211521
2009 Xenopus Meis3 protein lies at a nexus downstream to Zic1 and Pax3 proteins, regulating multiple cell-fates during early nervous system development. Developmental biology 30 19944089
2003 Expression of ZIC genes in the development of the chick inner ear and nervous system. Developmental dynamics : an official publication of the American Association of Anatomists 30 12666207
2013 Pax3 synergizes with Gli2 and Zic1 in transactivating the Myf5 epaxial somite enhancer. Developmental biology 29 24036067
2013 ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 29 24457242
2010 Expression of the zic1, zic2, zic3, and zic4 genes in early chick embryos. BMC research notes 29 20553611
2008 C2H2 zinc finger genes of the Gli, Zic, KLF, SP, Wilms' tumour, Huckebein, Snail, Ovo, Spalt, Odd, Blimp-1, Fez and related gene families from Branchiostoma floridae. Development genes and evolution 29 18795322
2011 Role of BMP, FGF, calcium signaling, and Zic proteins in vertebrate neuroectodermal differentiation. Neurochemical research 28 21336820
2016 Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors. International journal of oncology 27 27572108
2007 The Zic family member, odd-paired, regulates the Drosophila BMP, decapentaplegic, during adult head development. Development (Cambridge, England) 27 17329368
2012 Comparison of ZIC-HILIC and graphitized carbon-based analytical approaches combined with exoglycosidase digestions for analysis of glycans from monoclonal antibodies. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 26 23217312
2017 Zic-Proteins Are Repressors of Dopaminergic Forebrain Fate in Mice and C. elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 28972122
2015 A Brn2-Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells. Journal of cell science 25 25991548
2013 The MYC, TERT, and ZIC1 genes are common targets of viral integration and transcriptional deregulation in avian leukosis virus subgroup J-induced myeloid leukosis. Journal of virology 25 24371071
2007 Dicyema Pax6 and Zic: tool-kit genes in a highly simplified bilaterian. BMC evolutionary biology 25 17961212
2016 Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1. Scientific reports 24 27881878
2011 The role of Zic family zinc finger transcription factors in the proliferation and differentiation of retinal progenitor cells. Biochemical and biophysical research communications 24 22024047
2018 Role of Zic Family Proteins in Transcriptional Regulation and Chromatin Remodeling. Advances in experimental medicine and biology 23 29442331
2018 ZIC1 acts a tumor suppressor in breast cancer by targeting survivin. International journal of oncology 23 29956756
2012 ZIC-cHILIC as a fractionation method for sensitive and powerful shotgun proteomics. Nature protocols 23 23099486
2010 Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient. American journal of medical genetics. Part A 23 21204220
2007 Visualization of two distinct classes of neurons by gad2 and zic1 promoter/enhancer elements in the dorsal hindbrain of developing zebrafish reveals neuronal connectivity related to the auditory and lateral line systems. Developmental dynamics : an official publication of the American Association of Anatomists 23 17279576
2004 Possible roles of zic1 and zic4, identified within the medaka Double anal fin (Da) locus, in dorsoventral patterning of the trunk-tail region (related to phenotypes of the Da mutant). Mechanisms of development 22 15210192
2018 Comparative Genomics of the Zic Family Genes. Advances in experimental medicine and biology 21 29442314
2016 Roles of ZIC family genes in human gastric cancer. International journal of molecular medicine 21 27177248
2006 The zic1 gene is expressed in chick somites but not in migratory neural crest. Gene expression patterns : GEP 21 16451832

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