Regulation of mammalian brain development by p21-activated kinase signaling pathways

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Title: Regulation of mammalian brain development by p21-activated kinase signaling pathways******This application is a renewal of my current NSERC discovery grant (RGPIN341498, 2012-2017).******The long-term goal of my research program is to understand the fundamental mechanisms that govern brain development and function. To this end, we have identified a number of molecules that are important for neuronal proliferation, survival, migration, morphogenesis and maturation, a series of highly regulated processes critical for normal brain growth, neural circuit formation and function. With particular relevance to this application and with the funding of my current NSERC discovery grant (2012-17), we have demonstrated that knockout (KO) mice lacking the p21-activated kinases (PAKs), a family of protein kinases known to be important for cytoskeletal reorganization, are altered in brain size, cortical volume, neuronal progenitor cell division and migration. Significantly, these KO mice are defective in the activity of LIM-kinase 1 (LIMK1) and the actin-binding protein cofilin, both of which are key targets of PAKs important for actin regulation. Furthermore, we discovered that PAKs can exert effects on the endocannabinoid (eCB) system, an emerging player in various aspects of embryonic brain development. These results lead to a hypothesis that PAKs regulate cortical development via coordinating actin reorganization and eCB signaling. To address this hypothesis, we will use multiple techniques, including mouse genetics, immunohistochemistry, imaging, biochemical assays and electrophysiological recordings to achieve three specific aims: ******Aim 1. To determine the relative contribution of PAK1 and 3 in neuronal proliferation and migration by labeling and tracking neural progenitor cells in various PAK KO mice. ******Aim 2. To determine the role of PAK1 and 3 in early postnatal neuronal morphogenesis and synaptic maturation by analyzing neuronal and synaptic morphology. ******Aim 3. To elucidate the molecular mechanisms underlying PAK1/3 actions by investigating the role of LIMK1/cofilin and eCB signaling.******The results from this application will reveal the in vivo function and underlying mechanisms by which PAK signaling regulates cortical and neuronal development. This will in turn contribute to my long-term goal to understand the fundamental process governing brain development and function. Since both cortical malformations and PAKs are closely associated with many neurological and mental disorders, this proposal will also provide new insight into the pathogenesis and treatment of these diseases. ********