ZIC3 explained

ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family.[1] [2]

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,[3] [4] 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.[5] 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 [6] as well indicated a role for Zic3 in neural crest specification. [7] Both the left-right defects and the neural tube defects caused by loss of Zic3 have been linked to defective planar cell polarity. [8]

ZIC3 is also of particular interest as it has been shown to be required for maintenance of embryonic stem cell pluripotency.[9]

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.[10] 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.[11] Such a role is of critical importance, as not only is correct Wnt signalling critical for early development,[12] 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.[13]

Further reading

Notes and References

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

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