Dandy-Walker Malformation (DWM) is the most frequently occurring birth defect that causes developmental malformations of the cerebellum and hindbrain, leading to mental retardation or developmental delay. We have recently identified two members of the Zic transcription factor encoding gene family as strong DWM candidate genes. The overall goal of this proposal is to provide insight into the developmental roles of these genes in the pathogenesis of DWM. Our general strategy is to define the developmental roles of these DWM candidate genes in vertebrate cerebellar and hindbrain development. We will use vertebrate models, coupled with in vitro approaches, to study Zic gene function and redundancy. In preliminary experiments we have constructed targeted mouse mutants for these Zic genes, and demonstrated that mutant mice lacking either of the Zic genes have cerebellar malformation phenotypes. We have also demonstrated that compound mutant mice have more severe cerebellar malformation phenotypes than those observed in either single mutant alone. These data indicate that the two Zic genes have genetically redundant function and that gene dosage is critical for normal cerebellar development. In this proposal, we have outlined a series of experiments to assess the developmental basis of the cerebellar malformations in single and compound mutant mice, based on extensive morphological, in situ and immunohistochemical analysis of hindbrain development. We will use in vitro assays to assess and compare transcriptional function of the two Zic proteins. We will then extend these studies in vivo using both gain and loss of function approaches in the tractable zebrafish model system to investigate transcriptional function and to test whether these genes are functionally redundant. These experiments will also allow us to assess conservation of the roles of these genes across vertebrate hindbrain development. By taking a multi-pronged approach to the analysis of Zic1 and Zic4 gene function in CNS development, we will make more rapid and significant progress than by focusing on a single model system alone. Not only are these studies of importance to basic developmental biology, they also have direct relevance to understanding the pathogenesis of cerebellar malformation disorders in humans ? ?
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