Protocadherin control of cell proliferation and differentiation

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ABSTRACT During development, the division of progenitor cells is tightly regulated in time and place to produce the appropriate number and types of cells; misregulation of proliferation or differentiation can lead to morphogenetic defects and a variety of developmental disorders. The δ-pcdhs are a family of homophilic cell adhesion molecules that have been linked to neurodevelopmental disorders, including autism and epilepsy. They have additionally been identified as tumor suppressor genes in an array of cancers. Our preliminary data reveal that mutant zebrafish lacking individual δ1-pcdhs (pcdh1a, pcdh7a or pcdh9) or δ2-pcdhs (pcdh17, pcdh18b or pcdh19) all display increased cell proliferation in the early neural tube, resulting in excess neurons later in development. In a preliminary study using in vivo timelapse, we show by direct observation that the spatiotemporal dynamics of cell divisions is altered in the mutants. We further provide evidence that the δ- pcdhs are regulators of the canonical Wnt signaling pathway and that both canonical Wnt signaling and the Wnt receptor Ryk are required for the increased proliferation in δ-pcdh mutants. This proposal will test the hypotheses that: 1) cell-cell interactions, mediated by δ-pcdhs, coordinate cell proliferation and neural progenitor cell dynamics in the neuroepithelium; and 2) δ-pcdhs influence cell proliferation by regulating canonical Wnt/β-catenin signaling through Ryk. These experiments will elucidate the mechanics of fundamental events in nervous system development and provide important insights both into the underlying causes of neurodevelopmental disease and to the role of δ-pcdhs in cancer.