Alternative titles; symbols
HGNC Approved Gene Symbol: ZIC4
Cytogenetic location: 3q24 Genomic coordinates (GRCh38) : 3:147,386,046-147,406,543 (from NCBI)
ZIC4 belongs to the ZIC family of proteins, which are involved in transcriptional regulation during development (Ishiguro et al., 2004).
Aruga et al. (1996) cloned Zic4 from a mouse cerebellum cDNA library. The deduced 353-amino acid protein has a calculated molecular mass of 38.7 kD. Northern blot analysis detected a faint Zic4 transcript only in mouse cerebellum. RNase protection assays detected strong Zic4 expression in cerebellum and weak expression in the region including diencephalon, mesencephalon, and metencephalon. Zic4 was expressed by day 12 of mouse embryonic development, and expression peaked at postnatal day 5.
Aruga et al. (1996) determined that, unlike other mouse Zic genes, Zic4 contains only 2 exons in the protein-coding region.
Gross (2018) mapped the ZIC4 gene to chromosome 3q24 based on an alignment of the ZIC4 sequence (GenBank BC126267) with the genomic sequence (GRCh38).
By interspecific backcross analysis, Aruga et al. (1996) mapped the mouse Zic4 gene to chromosome 9.
Using a gel mobility shift assay, Ishiguro et al. (2004) found that the zinc finger domains of mouse Zic4 and Zic5 (617896) bound a DNA sequence also bound by Zic1 (600470), Zic2 (603073), and Zic3 (300265). However, unlike Zic1, Zic2, and Zic3, Zic4 and Zic5 did not activate transcription in luciferase reporter assays following transient overexpression in 293T cells and 10T1/2 cells. Imfa (MDFI; 604971) has been shown to repress the transcriptional activities of Zic1, Zic2, and Zic3, but Zic4 and Zic5 did not coimmunoprecipitate with Imfa when overexpressed in 293T cells. Moreover, overexpression of Imfa did not alter nuclear localization of overexpressed Zic4 or Zic5 in NIH3T3 cells. Ishiguro et al. (2004) proposed that Zic4 and Zic5 lack an N-terminal domain found in Zic1, Zic2, and Zic3 that is involved in transcriptional activation and Imfa binding.
Grinberg et al. (2004) mapped deletions in the 3q2 region in several individuals with Dandy-Walker malformation (DWM; see 220200); and defined a critical region associated with this disorder that included the Zic1 (600470) and Zic4 genes. Mice with a heterozygous deletion of these 2 linked genes had a phenotype that closely resembles DWM.
Aruga, J., Yozu, A., Hayashizaki, Y., Okazaki, Y., Chapman, V. M., Mikoshiba, K. Identification and characterization of Zic4, a new member of the mouse Zic gene family. Gene 172: 291-294, 1996. [PubMed: 8682319] [Full Text: https://doi.org/10.1016/0378-1119(96)00111-4]
Grinberg, I., Northrup, H., Ardinger, H., Prasad, C., Dobyns, W. B., Millen, K. J. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nature Genet. 36: 1053-1055, 2004. [PubMed: 15338008] [Full Text: https://doi.org/10.1038/ng1420]
Gross, M. B. Personal Communication. Baltimore, Md. 2/28/2018.
Ishiguro, A., Inoue, T., Mikoshiba, K., Aruga, J. Molecular properties of Zic4 and Zic5 proteins: functional diversity within Zic family. Biochem. Biophys. Res. Commun. 324: 302-307, 2004. [PubMed: 15465018] [Full Text: https://doi.org/10.1016/j.bbrc.2004.09.052]