Role of Dab2IP in Brain Development

Dab2IP 在大脑发育中的作用

• 批准号: 7032609
• 负责人: RAMIN HOMAYOUNI
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032609
• 关键词: actins; apolipoprotein E; axon; biological signal transduction; cell migration; cerebellar disorders; cerebellum; dendrites; developmental genetics; developmental neurobiology; gene mutation; genetically modified animals; guanine nucleotide binding protein; guanosinetriphosphatases; laboratory mouse; neurogenesis; neurogenetics; neuronal guidance; protein localization; protein protein interaction; protein structure function; psychomotor function; single cell analysis; synaptogenesis; tissue /cell culture; very low density lipoprotein; actins; apolipoprotein E; axon; biological signal transduction; cell migration; cerebellar disorders; cerebellum; dendrites; developmental genetics; developmental neurobiology; gene mutation; genetically modified animals; guanine nucleotide binding protein; guanosinetriphosphatases; laboratory mouse; neurogenesis; neurogenetics; neuronal guidance; protein localization; protein protein interaction; protein structure function; psychomotor function; single cell analysis; synaptogenesis; tissue /cell culture; very low density lipoprotein

DESCRIPTION (provided by applicant): The mammalian brain is formed through a series of intricately orchestrated events whereby neurons born in germinal zones migrate great distances to reach their final positions and form specific connections. Abnormalities in neuronal migration and positioning are believed to be responsible in part for disorders such as lissencephaly, pediatric epilepsy, schizophrenia and autism. Recent genetic studies in mice have identified a key signaling pathway that controls cell positioning and formation of laminated structures throughout the mammalian brain. Mice with disruptions in reelin, disabled-1 (Dab1), or both very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) genes exhibit nearly identical histopathological abnormalities. Reelin is an extracellular protein that directly binds to the lipoprotein receptors and induces tyrosine phosphorylation of Dab1. Dab1 is an intracellular adapter protein that is required for Reelin signaling. The long-range goal of this project is to identify molecular components downstream of Dab1 in the Reelin signaling pathway and to understand the mechanism by which Reelin controls neuronal positioning, dendritic maturation, and synaptic function. Using a yeast two-hybrid strategy, it was found that Dab1 interacts with amyloid precursor family proteins, protocadherin-18 and the novel GTPase activating protein Dab2 interacting protein (Dab2IP). The deduced amino acid sequence of Dab2IP encodes a Ras GAP related domain and several protein-protein interaction domains, including an NPxY PTB-interacting motif. It is hypothesized that Dab2IP functions as a regulator of GTPases and, by virtue of its interaction with Dab1 and other intracellular proteins, is the downstream effector in the Reelin signaling pathway. The specific aims of this proposal are to: 1) Characterize the activity, regulation and cellular function of Dab2IP; 2) Determine if Dab2IP plays a critical role in Reelin signaling; 3) Characterize the Dab2IP-P1-/- mice which have recently been generated in this laboratory. Understanding the biological function of Dab2IP and its role in Reelin signaling will provide valuable insight into the molecular mechanisms of neuronal migration, cell positioning and dendrite maturation during brain development.

描述（由申请人提供）：哺乳动物的大脑是通过一系列精心策划的事件形成的，这些事件在生发区域中出生的神经元迁移了很大的距离以达到其最终位置并形成特定的连接。据信神经元迁移和定位的异常是部分造成诸如Lissphaly，小儿癫痫，精神分裂症和自闭症等疾病的原因。小鼠的近期遗传研究已经确定了一个关键的信号通路，该途径控制整个哺乳动物大脑的细胞定位和形成的细胞定位和形成。 reelin，disabled-1（DAB1）或非常低密度脂蛋白受体（VLDLR）和珠脂蛋白E受体2（APOER2）基因的小鼠表现出几乎相同的组织病理学异常。 reelin是一种直接与脂蛋白受体结合并诱导DAB1酪氨酸磷酸化的细胞外蛋白。 DAB1是reelin信号所需的细胞内适配器蛋白。该项目的远距离目标是确定reelin信号通路中DAB1下游的分子成分，并了解Reelin控制神经元定位，树突成熟和突触功能的机制。使用酵母双杂交策略，发现DAB1与淀粉样蛋白前体蛋白，Protocadherin-18和新型GTPase激活蛋白DAB2相互作用蛋白（DAB2IP）相互作用。 DAB2IP的推导氨基酸序列编码RAS间隙相关结构域和几个蛋白质 - 蛋白质相互作用结构域，包括NPXY PTB相互作用基序。假设DAB2IP充当GTPase的调节剂，并且由于它与DAB1和其他细胞内蛋白的相互作用是Reelin信号通路中的下游效应子。该建议的具体目的是：1）表征DAB2IP的活性，调节和细胞功能； 2）确定dab2ip在reelin信号传导中是否起关键作用； 3）表征该实验室最近生成的DAB2IP-P1 - / - 小鼠。了解DAB2IP的生物学功能及其在reelin信号传导中的作用将提供对脑发育过程中神经元迁移，细胞定位和树突成熟的分子机制的宝贵见解。