REGULATION OF NEURONAL DEVELOPMENT BY UBIQUITIN PATHWAYS

这项拟议的研究的长期目标是阐明调节 哺乳动物大脑中的树突形态发生。我们最近发现，泛素 连接酶CDC20-后期促进复合体(CDC20-APC)促进细胞的产生和 哺乳动物有丝分裂后神经元中树突状突起的形成。Cdc20基因敲除 在小脑片和出生后大鼠小脑中的体内RNAi显示了一种必要的 Cdc20在枝晶生长和树枝形成中的作用。值得注意的是，CdC20集中在 神经元的中心体和中心体的定位是神经元CdC20- APC来驱动枝晶的发展。这些发现提出了几个基本问题 CDC20-APC的新功能在神经元中是如何调节的以及CDC20-APC是如何 协调树枝状晶体的发育。为了解决这些问题，我们建议找出关键 影响CDC20-APC功能的结构域和翻译后修饰 在树枝晶形态发生中。我们还将鉴定神经元CDC20-APC的底物 控制枝晶生长和细化。最后，根据初步证据，我们将 Cdc20-APC在树突重塑和图案化中的发育作用 小脑皮层。这项拟议的研究代表了一系列重要的实验 将解决我们对构成细胞内在机制的理解中的一个重大差距 神经元的形态发生和连接。此外，由于枝晶的异常 形态学被认为与多种神经性和非神经性 精神障碍，包括神经退行性疾病和智力低下， 拟议的研究应该为更好地了解这些疾病提供基础。

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.