Molecular Mechanisms That Control Neuronal Positioning

发育过程中神经元位置的紊乱可能会对神经系统的功能造成毁灭性的影响。相对轻微的神经元异位可导致癫痫，而广泛的神经元发育不良可导致严重的智力低下。该项目研究在胚胎大脑发育过程中调节神经元迁移和定位的分子机制。特别是，我们专注于一个分子级联，它涉及至少4个已知的基因产物，它们传递调节迁移神经元的细胞属性的信号，并将它们引导到适当的层。这些蛋白质包括一种细胞外蛋白Reelin，它是在发育中的大脑的不同区域产生的；ApoER2和VLDL2两种跨膜受体；以及Dab1，一种细胞质信号分子。Reelin与受体结合诱导Dab1酪氨酸磷酸化。我们发现，Dab1的酪氨酸磷酸化促进了Dab1和SH2结构域分子之间的相互作用，如Nckβ和Crk。这些分子此前已被证明与调节细胞骨架动力学的分子相互作用。我们目前正在建立模型，以确定这些分子在神经元放置中的作用。实验室的另一个兴趣是这些分子在成人神经系统维护中的作用。为了研究这一点，我们开发了一种小鼠系，它含有Dab1的条件等位基因，可以通过Cre重组酶的调节表达而失活。这项工作的目标是在神经系统中正确形成Dab1后使其失活，并确定这是否会导致任何神经系统功能障碍。

Disorders in the placement of neurons during development can be devastating to the function of the nervous system. Relatively mild neuronal ectopias can lead to epilepsy while widespread neuronal dysplasias lead to severe mental retardation. This project studies the molecular machinery that regulates the migration and positioning of neurons during embryonic brain development. In particular, we are focused on a molecular cascade that involves at least 4 known gene products that relay a signal that regulates the cellular properties of migrating neurons and direct them to the appropriate layers. These proteins include a extracellular protein Reelin, that is produced in discrete regions of the developing brain, ApoER2 and VLDL2 two membrane spanning receptors and Dab1 a cytoplasmic signaling molecule. The binding of Reelin to the receptors induces the tyrosine phosphorylation of Dab1. We have found tyrosine phosphorylation of Dab1 fosters interactions between Dab1 and SH2 domain molecules such as Nckbeta and Crk. These molecules have previously been shown to interact with molecules that regulate cytoskeletal dynamics. We are currently establishing models to determine the role of these molecules in neuronal placement. Another interest in the lab is the role of these molecules in the maintenance of the adult nervous system. To study this we have developed a mouse line that harbors a conditional allele for Dab1, that can be inactivated by the regulated expression of the Cre recombinase. The goal of this work is to inactivate Dab1 in the nervous system after it has formed correctly, and determine if this causes any nervous system dysfunction.