Molecular basis of Zic-mediated developmental control

ZIC基因是已知的全前脑畸形、Dandy-Walker畸形和异位症的致病基因。在本研究中，我们对Zic基因家族的以下几个点进行了讨论。(1)新的Zic结合蛋白的鉴定；(2)Zic和Zic结合蛋白之间相互作用的生物学意义；(3)Zic蛋白的翻译后修饰；(4)与Zic蛋白有接触点的生物信号。酵母双杂交筛选鉴定I-MFA为ZIC抑制因子。(2，3)HMW分子络合物中Zic2-激酶的鉴定。Zic2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被鉴定，并通过质谱分析进行了表征。(4)通过分析Zic1/3和Zic2/3复合突变小鼠(Inoue等人，2007a；2007b)，研究了Zic相关的生物信号。特别是，我们揭示了Zic1和Zic3在前脑神经元前体的扩张中起着关键作用。WNT信号可能参与Zic介导的发育调控。此外，还研究了脊椎动物Zic基因在小鼠和非洲爪哇中的功能相似性和差异(Ishiguro等人，2004年；Fujimi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).