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源地迁移到它们整合到功能网络中的区域。已经鉴定了许多调节离散迁移事件的基因。神经元迁移的失败可导致从癫痫到智力迟钝的严重程度不等的疾病。 我的实验室研究了编码调节神经元定位的信号级联反应组分的基因，包括细胞外配体Reelin;两种受体ApoER 2和VLDLR;以及细胞质对接蛋白Dab 1。这种信号通路调节神经元在包括大脑皮层、海马和小脑在内的几个大脑区域中的定位。我们一直在努力扩大对途径组成部分的理解。 我们已经证明了Dab 1和APP在小鼠发育中的遗传相互作用，使用在实验室中产生的亚纯型Dab 1等位基因。我们发现APP的过度表达导致Dab 1亚型表型的恶化。相反，APP功能丧失部分挽救了轻度Dab 1表型。这提供了证据表明，与阿尔茨海默病有关的APP基因影响了控制大脑发育的分子途径。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家族的衔接蛋白在Reelin调节的神经突延伸中的作用。使用干扰Crk和相对CrkL表达的siRNA，我们已经表明这些分子是Reelin介导的树突延伸所需的，但它们不是轴突发生所需的。这项工作证明了Crk和CrkL在Dab 1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.