Molecular Mechanisms That Control Neuronal Positioning During Development

在哺乳动物大脑的发育过程中，大多数神经元从它们的起始点迁移到它们整合成功能网络的区域。已经确定了一些调节离散迁徙事件的基因。神经元迁移失败可能导致严重的疾病，从癫痫到智力低下。 我的实验室研究了编码调节神经元定位的信号级联的基因，包括细胞外配体Reelin；两个受体ApoER2和VLDLR；以及细胞质对接蛋白Dab1。这个信号通路调节几个大脑区域的神经元的位置，包括大脑皮层、海马体和小脑。我们一直在努力扩大对这条途径的组成部分的理解。 我们使用实验室中产生的亚型Dab1等位基因，在小鼠发育中证明了Dab1和APP之间的遗传相互作用。我们发现APP的过度表达导致Dab1亚型的恶化。相反，功能丧失的APP部分挽救了轻度Dab1表型。这提供了与阿尔茨海默病有关的APP基因影响控制大脑发育的分子途径的证据。我们目前正在努力确定导致这种遗传相互作用的分子机制。 我们研究了Crk接头蛋白家族在Reelin调节的轴突延伸中的作用。使用干扰Crk和相对CrkL表达的siRNAs，我们已经证明这些分子是Reelin介导的树突延伸所必需的，但它们不是轴突发生所必需的。这项工作证明了Crk和CrkL在Dab1酪氨酸磷酸化下游的Reelin信号通路中的作用。

During the development of the mammalian brain the majority of neurons migrate away from their sites of origin to regions where they become integrated into functional networks. A number of genes that regulate discrete migration events have been identified. Failures in neuronal migration can lead to diseases ranging in severity from epilepsy to mental retardation. My lab investigates the genes that encode components of a signaling cascade that regulate neuronal positioning, including an extracellular ligand, Reelin; two receptors, ApoER2 and VLDLR; and a cytoplasmic docking protein, Dab1. This signaling pathway regulates the positioning of neurons in several brain regions including the cerebral cortex, the hippocampus, and the cerebellum. We have worked to extend the understanding of the components of the pathway. We have demonstrated genetic interactions between Dab1 and APP in mouse development, using a hypomorphic Dab1 allele generated in the lab. We found that overexpression of APP lead to a worsening of the Dab1 hypomorphic phenotype. In contrast, loss-of -function APP partially rescued the mild Dab1 phenotype. This provides evidence that the APP gene, which is involved in Alzheimers disease, influences a molecular pathway that controls brain development. We are currently working to determine the molecular mechanism that leads to this genetic interaction. We have examined the role for the Crk family of adaptor proteins in Reelin-regulated neurite extension. Using siRNAs that interfere with the expression of Crk and the relative CrkL we have shown that these molecules are required for Reelin-mediated dendrite extension, but they are not required for axonogenesis. This work demonstrates a role for Crk and CrkL in the Reelin-signaling pathway downstream of Dab1 tyrosine phosphorylation.