ZIC3

Last updated
ZIC3
Protein ZIC3 PDB 2EJ4.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ZIC3 , HTX, HTX1, VACTERLX, ZNF203, Zic family member 3
External IDs OMIM: 300265 MGI: 106676 HomoloGene: 55742 GeneCards: ZIC3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family. [5] [6]

Contents

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, [7] [8] 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. [9] 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 [10] as well indicated a role for Zic3 in neural crest specification. [11] Both the left-right defects and the neural tube defects caused by loss of Zic3 have been linked to defective planar cell polarity. [12]

ZIC3 is also of particular interest as it has been shown to be required for maintenance of embryonic stem cell pluripotency. [13]

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. [14] 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. [15] Such a role is of critical importance, as not only is correct Wnt signalling critical for early development, [16] 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. [17]

Related Research Articles

<span class="mw-page-title-main">Neural crest</span> Pluripotent embyronic cell group giving rise to diverse cell lineages

Neural crest cells are a temporary group of cells that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia.

<span class="mw-page-title-main">GLI2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. The protein encoded by this gene is a transcription factor.

<span class="mw-page-title-main">GLI3</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.

<span class="mw-page-title-main">Autoimmune regulator</span> Immune system protein

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

<span class="mw-page-title-main">TCF4</span> Protein-coding gene in the species Homo sapiens

Transcription factor 4 (TCF-4) also known as immunoglobulin transcription factor 2 (ITF-2) is a protein that in humans is encoded by the TCF4 gene located on chromosome 18q21.2.

<span class="mw-page-title-main">ZEB2</span> Protein-coding gene in the species Homo sapiens

Zinc finger E-box-binding homeobox 2 is a protein that in humans is encoded by the ZEB2 gene. The ZEB2 protein is a transcription factor that plays a role in the transforming growth factor β (TGFβ) signaling pathways that are essential during early fetal development.

<span class="mw-page-title-main">EGR2</span> Protein-coding gene in the species Homo sapiens

Early growth response protein 2 is a protein that in humans is encoded by the EGR2 gene. EGR2 is a transcription regulatory factor, containing three zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells. It is later expressed in the neural crest derived cells of the cranial ganglion. The protein encoded by Krox20 contains two cys2his2-type zinc fingers. Krox20 gene expression is restricted to the early hindbrain development. It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish. In addition, the amino acid sequence and most aspects of the embryonic gene pattern is conserved among vertebrates, further implicating its role in hindbrain development. When the Krox20 is deleted in mice, the protein coding ability of the Krox20 gene is diminished. These mice are unable to survive after birth and exhibit major hindbrain defects. These defects include but are not limited to defects in formation of cranial sensory ganglia, partial fusion of the trigeminal nerve (V) with the facial (VII) and auditory (VII) nerves, the proximal nerve roots coming off of these ganglia were disorganized and intertwined among one another as they entered the brainstem, and there was fusion of the glossopharyngeal (IX) nerve complex.

<span class="mw-page-title-main">PITX2</span> Protein-coding gene in the species Homo sapiens

Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.

<span class="mw-page-title-main">WNT3A</span> Protein-coding gene in the species Homo sapiens

Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.

<span class="mw-page-title-main">SNAI2</span> Protein

Zinc finger protein SNAI2 is a transcription factor that in humans is encoded by the SNAI2 gene. It promotes the differentiation and migration of certain cells and has roles in initiating gastrulation.

<span class="mw-page-title-main">SALL1</span> Protein-coding gene in the species Homo sapiens

Sal-like 1 (Drosophila), also known as SALL1, is a protein which in humans is encoded by the SALL1 gene. As the full name suggests, it is one of the human versions of the spalt (sal) gene known in Drosophila.

<span class="mw-page-title-main">SALL4</span> Protein-coding gene in the species Homo sapiens

Sal-like protein 4(SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.

<span class="mw-page-title-main">ZIC2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein ZIC2 is a protein that in humans is encoded by the ZIC2 gene. ZIC2 is a member of the Zinc finger of the cerebellum (ZIC) protein family.

<span class="mw-page-title-main">ZIC1</span> Protein-coding gene in the species Homo sapiens

ZIC1 is a member of the Zinc finger of the cerebellum (ZIC) protein family.

<span class="mw-page-title-main">ZNF423</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein 423 is a protein that in humans is encoded by the ZNF423 gene.

<span class="mw-page-title-main">GBX2</span> Protein-coding gene in the species Homo sapiens

Homeobox protein GBX-2 is a protein that in humans is encoded by the GBX2 gene.

<span class="mw-page-title-main">CDON</span> Protein-coding gene in the species Homo sapiens

Cell adhesion molecule-related/down-regulated by oncogenes is a protein that in humans is encoded by the CDON gene.

<span class="mw-page-title-main">SHROOM3</span> Protein-coding gene in the species Homo sapiens

Protein shroom3 also known as shroom-related protein is a protein that in humans is encoded by the SHROOM3 gene.

<span class="mw-page-title-main">Retinal homeobox protein Rx</span> Protein-coding gene in the species Homo sapiens

Retinal homeobox protein Rx also known as retina and anterior neural fold homeobox is a protein that in humans is encoded by the RAX gene. The RAX gene is located on chromosome 18 in humans, mice, and rats.

<span class="mw-page-title-main">ZIC5</span>

ZIC5 is a member of the Zinc finger of the cerebellum (ZIC) protein family. ZIC5 is located on chromosome 13 in a divergently transcribed gene pair with the closely related gene ZIC2. It has been suggested that this tandem arrangement allows ZIC2 and ZIC5 to share regulatory elements and causes the two genes to have very similar expression patterns.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000156925 - Ensembl, May 2017
  2. 1 2 3 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.
  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