Regulation of mammalian brain development by p21-activated kinases

我的研究项目的长期目标是了解大脑发育和功能的分子机制。为此，我们一直在识别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控过程。在这项应用中，我们将研究p21活化激酶（PAKs）在小鼠皮质发育过程中调控神经元迁移和形态发生中的作用和潜在机制。PAKs是一个丝氨酸/苏氨酸蛋白激酶家族，已知在多种信号传导和细胞过程中起重要作用，特别是在肌动蛋白细胞骨架的调节中。然而，PAKs在哺乳动物大脑发育中的作用仍然难以捉摸。我们发现，缺乏PAK1和PAK3 （PAK家族蛋白的主要脑亚型）的敲除小鼠，其脑大小显著减小，皮质组织改变，神经元数量和形态减少。此外，PAKs的下游靶点肌动蛋白结合蛋白cofilin的活性在这些小鼠中也发生了显著改变，该蛋白是肌动蛋白重组的有效调节剂。因此，我们假设PAK1/3通过动作蛋白依赖的神经元迁移和形态发生来调节皮质发育。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，生化分析和电生理分析。这项应用的结果将揭示PAK信号调节皮质和神经元发育的体内作用和潜在机制。由于皮质畸形和PAKs与许多神经和精神疾病密切相关，本研究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.