Regulation of mammalian brain development by p21-activated kinases

我的研究计划的长期目标是了解大脑发育和功能的分子机制。为此，我们一直在鉴定和表征一系列对神经元增殖、存活、迁移、形态发生和成熟至关重要的分子，这些分子是一系列对正常大脑生长、神经回路形成和功能至关重要的高度调节的过程。在这个应用程序中，我们将调查的作用和潜在的机制p21激活激酶（PAKs）在调节神经元迁移和形态发生在小鼠皮层发育。PAK是丝氨酸/苏氨酸蛋白激酶家族，已知其对于多种信号传导和细胞过程，特别是在肌动蛋白细胞骨架的调节中是重要的。然而，PAKs在哺乳动物脑发育中的作用仍然是难以捉摸的。我们已经发现，缺乏PAK家族蛋白的主要脑同种型PAK 1和PAK 3的敲除小鼠的脑尺寸显著减小，皮质组织改变，神经元数量和形态减少。此外，PAK的下游靶标，肌动蛋白结合蛋白cofilin和肌动蛋白重组的有效调节剂的活性在这些小鼠中也发生了显著改变。因此，我们假设PAK 1/3通过肌动蛋白依赖的神经元迁移和形态发生调节皮质发育。为了解决这一假设，我们将采用多种技术，包括小鼠遗传学，免疫组织化学，成像，生化测定和电生理分析。从这个应用程序的结果将揭示在体内的作用和潜在的机制，PAK信号调节皮层和神经元的发育。由于皮质畸形和PAK与许多神经和精神障碍密切相关，因此该建议也将为这些疾病的发病机制和治疗提供新的见解。

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.