The role of gap junction proteins in the regulation of neural stem and progenitor cell proliferation and neuronal migration are the subjects of the current proposal. It has long been known that neuroepithelial cells in the developing cortex express gap junction proteins and are coupled by gap junction channels to other cells, but the role of coupling is not well understood. We have developed a set of molecular tools to address this issue. The experiments in the current proposal build on our preliminary results to explore how gap junction coupling regulates proliferation, migration and fate determination in the developing embryonic neocortex. We have designed and tested a set of RNAi constructs that are able to knock-down expression of each of the connexin subunits known to be expressed by embryonic neural stem and progenitor cells. We also constructed and tested the necessary mutant RNAi controls and introduced these constructs, singly and in combination, into proliferate cells in the in vivo developing cerebral cortex using in utero, intraventricular injection and electroporation. Inspection of the developing brain following variable survival intervals has demonstrated remarkable cellular effects of the loss-of-function strategy, including alterations in glial-guided migration, progenitor cell proliferation, and neurogenesis. We propose to refine a set of molecular tools to disrupt gap junction function in order to test a series of hypotheses concerning cortical development, including that gap junction communication mediates radial glial cell proliferation, couples migrating neurons to radial glial guides, promotes the generation of neurons, and mediates small molecule exchange between progenitor cells and immature neurons. The specific experiments outlined in this proposal will provide new information concerning the way neurons and progenitor cells interact at embryonic stages of brain development. Many human neurodevelopment disorders are associated with defects in neurogenesis and migration, ranging from severe malformations with mental retardation and epilepsy, to more subtle disorders such as autism and dyslexia. The results of this study may help shed light on mechanisms relevant to the etiology of many of them. ? ? ?
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