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调节树突形态发生的机制。我们最近发现，泛素连接酶Cdc 20-后期促进复合物（Cdc 20-APC）促进有丝分裂后哺乳动物神经元树突的产生和加工。在小脑切片和出生后大鼠小脑中通过RNAi基因敲低Cdc 20揭示了Cdc 20在树突生长和树枝化中的重要功能。值得注意的是，Cdc 20集中在神经元的中心体，并且中心体定位是神经元Cdc 20- APC驱动树突发育所必需的。这些发现提出了几个基本问题，Cdc 20-APC的新功能如何在神经元中调节，以及Cdc 20-APC如何协调树突发育。为了解决这些问题，我们建议确定的关键结构域和翻译后修饰Cdc 20有助于Cdc 20-APC功能的树突形态发生。我们还将确定神经元Cdc 20-APC的控制树突生长和阐述的基板。最后，基于初步的证据，我们将描述的发展作用的Cdc 20-APC在小脑皮质树突重塑和图案。拟议的研究代表了一组重要的实验，将解决我们对神经元形态发生和连接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精神发育迟滞，拟议的研究应该提供更好地了解这些疾病的基础。公共卫生相关性：树突是神经元的重要接受肢，因此树突的形态对于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，不仅对于更好地理解大脑发育至关重要，而且对于深入了解整个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.