Regulation of mammalian brain development by p21-activated kinases

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The long-term goal of my research program is to understand the molecular mechanisms underlying brain development and function. To this end, we have been identifying and characterizing a series 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. In this application, we will investigate the role and underlying mechanisms of p21-activated kinases (PAKs) in the regulation of neuronal migration and morphogenesis during mouse cortical development. PAKs are a family of serine/threonine protein kinases known to be important for multiple signaling and cellular processes, particularly in the regulation of the actin cytoskeleton. However, the role of PAKs in mammalian brain development remains elusive. We have discovered that the knockout mice lacking PAK1 and PAK3, the predominant brain isoforms of the PAK family proteins, are dramatically reduced in brain size with altered cortical organization, reduced neuronal number and morphology. In addition, the activity of a downstream target of PAKs, the actin-binding protein cofilin and a potent regulator of actin reorganization, is also significant altered in these mice. We therefore hypothesize that PAK1/3 regulate cortical development via actin-dependent neuronal migration and morphogenesis. To address this hypothesis, we will employ multiple techniques, including mouse genetics, immunohistochemistry, imaging, biochemical assays and electrophysiological analysis. The results from this application will reveal the in vivo role and underlying mechanisms by which PAK signaling regulates cortical and neuronal development. 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.