The Role of Fzd9 in Hippocampal and Cortical Development

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DESCRIPTION (provided by applicant): Frizzled9, a Wnt receptor gene, is within the chromosomal deletion interval for Williams syndrome in humans. Symptoms of this disease include visuospatial processing defects and a high incidence of seizures. Work from the Pleasure laboratory has recently demonstrated that mice with mutations in Frizzled9 have developmental defects in the dentate gyrus, including excess cell death that result in a small decrease in the number of dentate granule neurons. These mice also have profound visualspatial learning deficits and lowered seizure threshold, mimicking symptoms of Williams Syndrome patients; hence, it seems likely that Frizzled9 function is critical in this syndrome. Wnts have important roles in regulating dendritic, axonal, and synaptic morphology, and Fzd9 is expressed throughout the hippocampus and posterior neocortex. Hence, Fzd9 transgenic mice may have more widespread defects than has already been demonstrated. The current research proposal will build on the previous studies of Fzd9 function by working toward answering three questions: 1. Does Frizzled9 regulate hippocampal and cortical anatomy? 2. Does Frizzled9 have functions in the adult brain? and 3. Does canonical Wnt signaling regulate the morphological differentiation or survival of immature neurons in the dentate gyrus? To accomplish these goal I will examine the detailed cellular neuroanatomy and connectivity of the hippocampus and neocortex in Fzd9 mutants. In addition, I will generate conditional loss-of-function and gain-of-function mutants to examine the role of Fzd9 during development and in adulthood. This may demonstrate that adult re-expression of Fzd9 in mutant mice can rescue some of the behavioral deficits due to a loss of Fzd9 function during development. Finally, I will investigate the effects of Wnt overexpression to better understand its role in neurodevelopment. Frizzled9 is one of approximately 20 genes deleted in Williams syndrome; therefore, understanding its function is critical to discerning its role in this condition. This neurodevelopmental disorder is characterized by a friendly, effusive personality, enhanced language ability and impaired spatial cognition. Since in many ways the most preserved functions in these patients are the exact ones most impaired in autistic patients, some have suggested that there are likely to be important lessons for autism to be learned from this other important neurodevelopmental syndrome. These studies will help to further our understanding of both of these significant developmental disorders.