Role of Dab2IP in Brain Development

描述（由申请人提供）：哺乳动物的大脑是通过一系列复杂的协调事件形成的，在萌芽区出生的神经元迁移很远的距离到达它们的最终位置并形成特定的连接。神经迁移和定位异常被认为是造成无脑畸形、小儿癫痫、精神分裂症和自闭症等疾病的部分原因。最近对小鼠的遗传研究已经确定了控制哺乳动物大脑中细胞定位和层压结构形成的关键信号通路。reelin, disability -1 （Dab1）或极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2 （ApoER2）基因破坏的小鼠表现出几乎相同的组织病理异常。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信号传递所必需的细胞内适配蛋白。该项目的长期目标是确定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。利用酵母双杂交策略，发现Dab1与淀粉样蛋白前体家族蛋白、原钙粘蛋白-18和新型GTPase激活蛋白Dab2相互作用蛋白（Dab2IP）相互作用。Dab2IP的氨基酸序列编码一个Ras GAP相关结构域和多个蛋白质相互作用结构域，包括一个NPxY ptb相互作用基序。据推测，Dab2IP作为gtpase的调节因子，通过与Dab1和其他细胞内蛋白的相互作用，是Reelin信号通路的下游效应因子。本提案的具体目的是：1)表征Dab2IP的活性、调控和细胞功能；2)确定Dab2IP是否在Reelin信号传导中起关键作用；3)对本实验室新近培养的Dab2IP-P1-/-小鼠进行表征。了解Dab2IP的生物学功能及其在Reelin信号传导中的作用，将为了解大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提供有价值的见解。

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.