Role of the Zic2 gene in CNS development & malformation

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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.