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Abstract. Zic3 is a C^sub 2^H^sub 2^ zinc finger transcription factor that is involved in early patterning of the vertebrate embryo. Human patients with mutations in the X-linked ZIC3 gene have a complex developmental phenotype that includes laterality defects, congenital heart disease, and lumbosacral and anal anomalies, including neural tube defects. Similar phenotypes are found in the bent tail (Bn) mouse, a spontaneous mutation that is associated with a submicroscopic deletion of the Zic3 locus, as well as in a Zic3 null allele generated through homologous recombination. These findings suggest that Zic3 plays important roles during development in establishing a proper left-right axis and in midline neural patterning. This review will summarize our current understanding of the role of Zic3 in patterning of the vertebrate embryo, based on studies in model organisms such as Xenopus and the mouse. In addition, a comparison of Zic3 with other vertebrate Zic family members will be provided.
The Zic gene family
Zic3 (for zinc finger in the cerebellum 3) is a member of the GLI superfamily of transcription factors (Aruga et al., 1996a). Based on their amino acid sequences and conserved gene structures, Zic genes likely share a common ancestor with the Drosophila pair-rule gene odd-paired (opa) (mammalian Zic genes are designated by symbols for the murine loci unless otherwise indicated). Opa is involved in the development of visceral mesoderm and in establishing alternate parasegments in the Drosophila embryo and is required for the timely activation of engrailed and wingless (Benedyk et al., 1994; Cimbora and Sakonju, 1995).
Zic genes and proteins
The first mammalian Zic family member, Zic1, was identified upon screening an adult mouse cerebellum cDNA library. In the adult, all of the mammalian Zic genes are expressed almost exclusively in the cerebellum (Aruga et al., 1994, 1996a). Subsequently, additional vertebrate Zic genes were identified through low-stringency genomic screens and analysis of cDNA libraries (Aruga et al., 1996a, b; Furushima et al., 2000; Nakata et al., 2000). The five known mammalian and four Xenopus zic proteins each contain five tandem C^sub 2^H^sub 2^ zinc fingers that are highly conserved across species (see Fig. 1). The first zinc finger in all Zic proteins, as well as in opa, lacks the first conserved cysteine residue and is unlikely...