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精心安排的事件形成的，由此在生发区产生的神经元迁移很长的距离以到达它们的最终位置并形成特定的连接。神经元迁移和定位的异常被认为是造成诸如无脑畸形、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一个关键的信号通路，该通路控制整个哺乳动物大脑中细胞的定位和层状结构的形成。reelin、disabled-1（Dab 1）或极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2（ApoER 2）基因均被破坏的小鼠表现出几乎相同的组织病理学异常。Reelin是一种细胞外蛋白，其直接结合脂蛋白受体并诱导Dab 1的酪氨酸磷酸化。Dab 1是一种细胞内衔接蛋白，是Reelin信号传导所必需的。该项目的长期目标是识别Reelin信号通路中Dab 1下游的分子组分，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Dab 1与淀粉样蛋白前体家族蛋白原钙粘蛋白-18和新的GT3活化蛋白Dab 2相互作用蛋白（Dab 2 IP）相互作用。Dab 2 IP的推导氨基酸序列编码Ras GAP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。据推测，Dab 2 IP作为GTP酶的调节剂发挥作用，并且凭借其与Dab 1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。本提案的具体目的是：1）表征Dab 2 IP的活性、调节和细胞功能; 2）确定Dab 2 IP是否在Reelin信号传导中起关键作用; 3）表征本实验室最近产生的Dab 2 IP-P1-/-小鼠。了解Dab 2 IP的生物学功能及其在Reelin信号传导中的作用将为了解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.