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 skeletal defects.
ZIC3 is also of particular interest as it has been shown to be required for maintenance of embryonic stem cell pluripotency.
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.
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Houtmeyers R, Souopgui J, Tejpar S, Arkell R. (2013). "The ZIC gene family encodes multi-functional proteins essential for patterning and morphogenesis". Cell Mol Life Sci.70 (20): 3791–811. doi:10.1007/s00018-013-1285-5. PMID23443491.
Bedard JE, Purnell JD, Ware SM (2007). "Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3". Hum. Mol. Genet.16 (2): 187–98. doi:10.1093/hmg/ddl461. PMID17185387.
Zhu L, Harutyunyan KG, Peng JL et al. (2007). "Identification of a novel role of ZIC3 in regulating cardiac development". Hum. Mol. Genet.16 (14): 1649–60. doi:10.1093/hmg/ddm106. PMID17468179.CS1 maint: Explicit use of et al. (link)