Role of the Zic2 gene in CNS development & malformation

无前脑畸形(HPE)是一种严重的脑畸形，其中线结构在发育早期不能形成。我们最近证明了转录因子基因ZIC2的杂合突变(单倍体不足)会导致人类HPE，我们用转基因小鼠进行的研究也表明，Zic2表达模式和/或水平的改变会导致各种畸形，如脑外畸形、无脑和面部发育不全。这些结果表明，Zic2在中枢神经系统和面部发育中起着关键作用。尽管有证据表明，Zic2在发育早期起作用，并可能调节背神经管、神经脊和体节中某些细胞群的大小，但人们对包括Zic2在内的Zic基因如何在细胞或分子水平上发挥作用知之甚少。我们研究的长期目标是详细了解ZIC2表达变化是如何导致人类大脑畸形的。该方案中的实验旨在通过以下方式阐明Zic2在发育中的功能：1)在转基因小鼠模型中检测Zic2过表达的形态和分子效应；2)确定Zic2在鸡神经管中错误表达的细胞和分子效应；3)确定Zic2表达的潜在上游调控因子；以及4)探索对正常Zic2功能至关重要的蛋白质-蛋白质相互作用。完成后，我们提出的研究将填补我们目前对Zic2的作用以及它如何与其他发育途径相互作用的理解中的许多空白。此外，我们的研究将阐明导致HPE的细胞和分子过程，因此将有助于理解这种和其他脑畸形。

Holoprosencephaly (HPE) is a severe brain malformation in which midline structures fail to form during early development. We have recently demonstrated that heterozygous mutations (haploinsufficiency) of the transcription factor gene, ZIC2 cause HPE in humans, and our studies with transgenic mice also demonstrate that alterations in the pattern and/or level of Zic2 expression result in a variety of malformations such as exencephaly, anencephaly and facial hypoplasia. These results indicate that Zic2 has a critical role in CNS and facial development. Although evidence suggests that Zic2 acts early in development and may regulate the size of certain populations of cells in the dorsal neural tube, neural crest and somites, little is known about how the Zic genes, including Zic2, function at a cellular or molecular level. The long term goal of our research is to develop a detailed understanding of how altered ZIC2 expression results in human brain malformation. Experiments in this proposal are designed to elucidate Zic2 function in development by: 1) Examining the morphologic and molecular effects of Zic2 over-expression in a transgenic mouse model; 2) Determining the cellular and molecular effects of Zic2 mis-expression in the chick neural tube; 3) Determining potential upstream regulators of Zic2 expression; and 4) Exploring the protein-protein interactions that are essential for normal Zic2 function. When completed, the studies we propose will fill in many of the gaps in our present understanding of the role of Zic2 and how it interacts with other developmental pathways. In addition, our studies will elucidate the cellular and molecular processes that result in HPE and will therefore be useful in understanding this and other brain malformations.