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ZIC3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2EJ4, 2RPC
Identifiers
Aliases	ZIC3, HTX, HTX1, VACTERLX, ZNF203, Zic family member 3
External IDs	OMIM: 300265; MGI: 106676; HomoloGene: 55742; GeneCards: ZIC3; OMA:ZIC3 - orthologs
Gene location (Human) Chr. X chromosome (human) Band Xq26.3 Start 137,566,127 bp End 137,577,691 bp
Gene location (Mouse) Chr. X chromosome (mouse) Band X A6|X 32.56 cM Start 57,068,060 bp End 57,087,096 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum testicle paraflocculus of cerebellum ventricular zone cerebellar vermis embryo ganglionic eminence optic nerve C1 segment Hypothalamus Top expressed in primitive streak Epithelium of choroid plexus ciliary body epiblast iris tail of embryo choroid plexus of fourth ventricle lumbar subsegment of spinal cord Rostral migratory stream lateral septal nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding DNA binding nucleic acid binding sequence-specific DNA binding metal ion binding DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific RNA polymerase II cis-regulatory region sequence-specific DNA binding RNA polymerase II transcription regulatory region sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component cytoplasm nucleus nucleoplasm Biological process determination of left/right symmetry somatic stem cell population maintenance determination of pancreatic left/right asymmetry nervous system development determination of digestive tract left/right asymmetry multicellular organism development heart looping cell differentiation regulation of transcription, DNA-templated anterior/posterior pattern specification determination of liver left/right asymmetry pattern specification process transcription, DNA-templated lung development determination of left/right asymmetry in nervous system positive regulation of transcription, DNA-templated positive regulation of transcription by RNA polymerase II transcription by RNA polymerase II central nervous system development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7547 22773 Ensembl ENSG00000156925 ENSMUSG00000067860 UniProt O60481 Q62521 RefSeq (mRNA) NM_003413 NM_001330661 NM_009575 RefSeq (protein) NP_001317590 NP_003404 NP_033601 Location (UCSC) Chr X: 137.57 – 137.58 Mb Chr X: 57.07 – 57.09 Mb PubMed search
Wikidata
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ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family.

ZIC3 is classified as a ZIC protein due to conservation of the five C2H2 zinc fingers, which enables the protein to interact with DNA and proteins. Correct function of this protein family in critical for early development, and as such mutations of the genes encoding these proteins is known to result in various congenital defects. For example, mutation of ZIC3 is associated with heterotaxy, that is thought to occur due to the role of ZIC3 in initial left-right symmetry formation, which involves the maintaining redistributed Nodal after the asymmetry of the embryo is initially broken. Mutation of ZIC3 is also associated with various heart defects, such as heart looping, however these are thought to represent a mild form of heterotaxy. Mouse based studies have linked defective ZIC3 with neural tube defects (spina bifida and exencephaly) and skeletal defects as well indicated a role for Zic3 in neural crest specification. Both the left-right defects and the neural tube defects caused by loss of Zic3 have been linked to defective planar cell polarity.

ZIC3 is also of particular interest as it has been shown to be required for maintenance of embryonic stem cell pluripotency.

Involvement in Wnt signalling

ZIC2, another member of the ZIC family, has recently been found to interact with TCF7L2, enabling it to act as a Wnt/β-catenin signalling inhibitor. Further experiments have indicated that human ZIC3 is also able to inhibit Wnt signalling and that the Zinc finger domains are absolutely critical for this role. Such a role is of critical importance, as not only is correct Wnt signalling critical for early development, Wnt signalling has also been found to be upregulated to several cancers. In addition Zic3 inhibition of canonical Wnt has recently been shown to have a role in specification of the neural crest in mice.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000156925 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000067860 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ali RG, Bellchambers HM, Arkell RM (November 2012). "Zinc fingers of the cerebellum (Zic): transcription factors and co-factors". The International Journal of Biochemistry & Cell Biology. 44 (11): 2065–2068. doi:10.1016/j.biocel.2012.08.012. PMID 22964024.
6. "Entrez Gene: ZIC3 Zic family member 3 heterotaxy 1 (odd-paired homolog, Drosophila)".
7. Ware SM, Peng J, Zhu L, Fernbach S, Colicos S, Casey B, et al. (January 2004). "Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects". American Journal of Human Genetics. 74 (1): 93–105. doi:10.1086/380998. PMC 1181916. PMID 14681828.
8. Bellchambers HM, Ware SM (2018). "ZIC3 in Heterotaxy". Zic family. Advances in Experimental Medicine and Biology. Vol. 1046. pp. 301–327. doi:10.1007/978-981-10-7311-3_15. ISBN 978-981-10-7310-6. PMC 8445495. PMID 29442328.
9. Ware SM, Harutyunyan KG, Belmont JW (June 2006). "Heart defects in X-linked heterotaxy: evidence for a genetic interaction of Zic3 with the nodal signaling pathway". Developmental Dynamics. 235 (6): 1631–1637. doi:10.1002/dvdy.20719. PMID 16496285. S2CID 1443795.
10. Purandare SM, Ware SM, Kwan KM, Gebbia M, Bassi MT, Deng JM, et al. (May 2002). "A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice". Development. 129 (9): 2293–2302. doi:10.1242/dev.129.9.2293. PMID 11959836.
11. Bellchambers HM, Barratt KS, Diamand KE, Arkell RM (September 2021). "SUMOylation Potentiates ZIC Protein Activity to Influence Murine Neural Crest Cell Specification". International Journal of Molecular Sciences. 22 (19): 10437. doi:10.3390/ijms221910437. PMC 8509024. PMID 34638777.
12. Bellchambers HM, Ware SM (November 2021). "Loss of Zic3 impairs planar cell polarity leading to abnormal left-right signaling, heart defects and neural tube defects". Human Molecular Genetics. 30 (24): 2402–2415. doi:10.1093/hmg/ddab195. PMC 8643499. PMID 34274973.
13. Lim LS, Hong FH, Kunarso G, Stanton LW (November 2010). "The pluripotency regulator Zic3 is a direct activator of the Nanog promoter in ESCs". Stem Cells. 28 (11): 1961–1969. doi:10.1002/stem.527. PMID 20872845. S2CID 35433304.
14. Pourebrahim R, Houtmeyers R, Ghogomu S, Janssens S, Thelie A, Tran HT, et al. (October 2011). "Transcription factor Zic2 inhibits Wnt/β-catenin protein signaling". The Journal of Biological Chemistry. 286 (43): 37732–37740. doi:10.1074/jbc.M111.242826. PMC 3199516. PMID 21908606.
15. Ahmed JN, Ali RG, Warr N, Wilson HM, Bellchambers HM, Barratt KS, et al. (May 2013). "A murine Zic3 transcript with a premature termination codon evades nonsense-mediated decay during axis formation". Disease Models & Mechanisms. 6 (3): 755–767. doi:10.1242/dmm.011668. PMC 3634658. PMID 23471918.
16. Fossat N, Jones V, Khoo PL, Bogani D, Hardy A, Steiner K, et al. (February 2011). "Stringent requirement of a proper level of canonical WNT signalling activity for head formation in mouse embryo". Development. 138 (4): 667–676. doi:10.1242/dev.052803. hdl:1885/66666. PMID 21228006.
17. Bellchambers HM, Barratt KS, Diamand KE, Arkell RM (September 2021). "SUMOylation Potentiates ZIC Protein Activity to Influence Murine Neural Crest Cell Specification". International Journal of Molecular Sciences. 22 (19): 10437. doi:10.3390/ijms221910437. PMC 8509024. PMID 34638777.

Further reading

• Bellchambers HM, Ware SM (2018). "ZIC3 in Heterotaxy". Zic family. Advances in Experimental Medicine and Biology. Vol. 1046. pp. 301–327. doi:10.1007/978-981-10-7311-3_15. ISBN 978-981-10-7310-6. PMC 8445495. PMID 29442328.
• Houtmeyers R, Souopgui J, Tejpar S, Arkell R (October 2013). "The ZIC gene family encodes multi-functional proteins essential for patterning and morphogenesis". Cellular and Molecular Life Sciences. 70 (20): 3791–3811. doi:10.1007/s00018-013-1285-5. hdl:1885/65873. PMID 23443491. S2CID 8660667.
• Bedard JE, Purnell JD, Ware SM (January 2007). "Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3". Human Molecular Genetics. 16 (2): 187–198. doi:10.1093/hmg/ddl461. PMID 17185387.
• Zhu L, Harutyunyan KG, Peng JL, Wang J, Schwartz RJ, Belmont JW (July 2007). "Identification of a novel role of ZIC3 in regulating cardiac development". Human Molecular Genetics. 16 (14): 1649–1660. doi:10.1093/hmg/ddm106. PMID 17468179.

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