Molecular basis of Zic-mediated developmental control

已知Zic基因是前脑无裂畸形、Dandy-Walker畸形和异位畸形的致病基因。本研究对Zic基因家族的以下几个方面进行了探讨。(1)Zic结合蛋白的发现、Zic与Zic结合蛋白之间相互作用的生物学意义、Zic蛋白的翻译后修饰、Zic蛋白的生物信号等方面的研究进展。(1)鉴定新的两种含Zic 2的高分子量分子络合物（Ishiguro等人，2007年）。通过酵母双杂交筛选鉴定I-mfa作为Zic-阻遏物。（2，3）高分子量分子复合物中Zic 2-激酶的鉴定。Zic 2蛋白的磷酸化在转录调控过程中起着关键作用。Zic蛋白中的其他修饰位点已经通过质谱分析鉴定和表征。(4)通过分析Zic 1/3和Zic 2/3复合突变小鼠来研究Zic相关的生物信号（Inoue等人，2007 a; 2007 b）。特别是，我们发现，Zic 1和Zic 3在前脑神经元前体的扩展中具有关键作用。Wnt信号可能参与Zic介导的发育调控。此外，已经在小鼠和非洲爪蟾中研究了脊椎动物Zic基因之间的功能相似性和差异（Ishiguro等人，2004;藤见等人，2006年）。

Zic genes are known for causal genes of holoprosencephaly, Dandy-Walker malformation, and heterotasxy.. In this study, following points of the Zic gene family have been dealt with. (1) Identification of novel Zic-binding proteins, (2) The biological significance of the protein-to-protein interaction between Zic and Zic-binding proteins, (3) Post-translational modification of Zic proteins, (4) Bio-signals that have contact points with Zic proteins.Following points were revealed and publicized in the scientific community.(1) Identification of novel two Zic2-containing high-molecular-weight molecular complexes (Ishiguro et al.,2007). Identification of I-mfa as a Zic-repressor by yeast two-hybrid screening. (2,3) Identification of a Zic2-kinase in the HMW molecular complexes. The phosphorylation of Zic2 protein was shown to be critical in the transcriptional regulatory processes. Other modifications sites in Zic proteins have been identified and characterized by mass spectrometry analysis. (4) The Zic related bio-signals was investigated by analyzing the Zic1/3 and Zic2/3 compound mutant mice (Inoue et al., 2007a; 2007b). In particular, we revealed that Zic1 and Zic3 have critical roles in the expansion of forebrain neuronal precursors. Wnt signals was suggested to be involved in the Zic mediated developmental control. In addition, functional similarity and difference among vertebrates Zic genes have been investigated in mouse and Xenopus (Ishiguro et al.,2004; Fujimi et al.,2006).