Regulation of Neuronal Development by Ubiquitin Pathways

描述（由申请人提供）：拟议研究的长期目标是阐明哺乳动物大脑中树突形态发生的调节机制。我们最近发现泛素连接酶cdc20 -后期促进复合体（Cdc20-APC）促进有丝分裂后哺乳动物神经元树突的产生和发育。通过RNAi在小脑切片和出生后小脑体内基因敲低Cdc20，揭示了Cdc20在树突生长和树突形成中的重要功能。值得注意的是，Cdc20集中在神经元的中心体上，而神经元Cdc20- APC驱动树突发育需要中心体定位。这些发现提出了关于Cdc20-APC的新功能如何在神经元中被调节以及Cdc20-APC如何协调树突发育的几个基本问题。为了解决这些问题，我们建议确定Cdc20中有助于Cdc20- apc在树突形态发生中的功能的关键结构域和翻译后修饰。我们还将确定控制树突生长和发育的神经元Cdc20-APC的底物。最后，基于初步证据，我们将描述Cdc20-APC在小脑皮层树突重塑和模式形成中的发育作用。提出的研究代表了一系列重要的实验，这些实验将解决我们对神经元形态发生和连接背后的细胞内在机制的理解中的一个主要空白。此外，由于树突形态异常被认为有助于多种神经和精神疾病的发病机制，包括神经退行性疾病和智力迟钝，因此提出的研究应为更好地理解这些疾病提供基础。公共卫生相关性：树突是神经元的关键接受肢，因此树突的形态对大脑中神经元回路的正常功能至关重要。我们建议确定支配枝晶发展的关键机制和原则。树突形态的异常可能与多种神经和精神疾病以及成人神经退行性疾病的发病机制有关。因此，了解树突是如何形成和成形的，不仅对更好地理解大脑发育至关重要，而且对了解一系列大脑疾病也至关重要。

DESCRIPTION (provided by applicant): The long-term goals of the proposed research are to elucidate the mechanisms that regulate dendrite morphogenesis in the mammalian brain. We recently discovered that the ubiquitin ligase Cdc20-anaphase promoting complex (Cdc20-APC) promotes the generation and elaboration of dendrites in postmitotic mammalian neurons. Genetic knockdown of Cdc20 by RNAi in cerebellar slices and in in vivo in the postnatal rat cerebellum revealed an essential function for Cdc20 in dendrite growth and arborization. Remarkably, Cdc20 is concentrated at the centrosome in neurons, and the centrosomal localization is required for neuronal Cdc20- APC to drive dendrite development. These findings have raised several fundamental questions on how the novel function of Cdc20-APC is regulated in neurons and how Cdc20-APC orchestrates dendrite development. To address these questions, we propose to identify the key domains and posttranslational modifications within Cdc20 that contribute to Cdc20-APC function in dendrite morphogenesis. We will also identify the substrates of neuronal Cdc20-APC that control dendrite growth and elaboration. Finally, based on preliminary evidence, we will characterize the developmental role of a Cdc20-APC in dendrite remodeling and patterning in the cerebellar cortex. The proposed research represents an important set of experiments that will address a major gap in our understanding of the cell-intrinsic mechanisms that underlie neuronal morphogenesis and connectivity. In addition, since abnormalities of dendrite morphology are thought to contribute to the pathogenesis of diverse neurological and psychiatric disorders, including neurodegenerative diseases and mental retardation, the proposed research should provide the foundation for a better understanding of these disorders. PUBLIC HEALTH RELEVANCE: Dendrites are the critical receptive limb of neurons and accordingly the morphology of dendrites is critical for the normal function of neuronal circuits in the brain. We propose to identify the key mechanisms and principles that govern dendrite development. Abnormalities of dendrite morphology may contribute to the pathogenesis of diverse neurological and psychiatric disorders as well as adult neurodegenerative disorders. Therefore, understanding how dendrites are form and shaped is not only essential for a better understanding of brain development but also for insights into a whole host of brain disorders.