Molecular Mechanisms That Control Neuronal Positioning

哺乳动物大脑的组织在很大程度上是由发育过程中神经元迁移的精确遗传控制决定的。调节神经元迁移的基因突变会导致严重程度不等的疾病，从癫痫到智力低下。这个项目的重点是决定神经元最终位置的分子机制。具体地说，我们研究了编码信号级联的组件的基因，其中包括细胞外配体Reelin；两个受体ApoER2和VLDLR；以及细胞质对接蛋白Dab1。Reelin与其受体结合导致Dab1酪氨酸磷酸化。我们已经鉴定了依赖于磷酸酪氨酸的Dab1结合蛋白，包括Crk和Nockb，并正在表征它们在Reelin信号转导中的作用。我们最近发现，降低神经元中的Crk水平会影响细胞对Reelin信号的一些反应。我们最近开发了Dab1的等位基因，这些等位基因有助于识别遗传交互作用和确定对Dab1的出生后需求。利用Dab1的亚型等位基因，我们一直在评估与淀粉样前体蛋白(APP)基因家族的遗传相互作用。之前已经证明了Dab1和APP之间的物理相互作用；然而，这种相互作用在发育过程中的作用尚不清楚。利用Dab1的条件等位基因，我们已经确定了Dab1在出生后的作用。在缺乏Dab1的情况下，小脑的出生后发育是异常的。利用Dab1的亚型和条件等位基因，我们将检查Dab1是否是成人神经系统功能(如学习和记忆)所必需的，我们还将检查Dab1和APP之间的遗传交互作用是否影响阿尔茨海默病？S病小鼠模型的退化。

The organization of the mammalian brain is determined in large part by precise genetic control of neuronal migration during development. Mutation in genes that regulate neuronal migration leads to disorders that range in severity from epilepsy to mental retardation. This project is focused on the molecular machinery that determines the final position of neurons. Specifically, we study the genes that encode components of a signaling cascade that includes an extracellular ligand, Reelin; two receptors, ApoER2 and VLDLR; and a cytoplasmic docking protein, Dab1. Binding of Reelin to its receptors leads to Dab1 tyrosine phosphorylation. We have identified phosphotyrosine-dependent Dab1 binding proteins, including Crk and Nckb, and are characterizing a role for them in Reelin signaling. We have recently shown that reducing Crk levels in neurons compromises some cellular responses to the Reelin signal. We have recently developed alleles of Dab1 that are useful for identifying genetic interactions and identifying postnatal requirements for Dab1. Using a hypomorphic allele of Dab1, we have been assessing genetic interactions with the amyloid precursor protein (APP) family of genes. Physical interactions between Dab1 and APP have been demonstrated previously; however, the function of this interaction during development is not known. Using a conditional allele of Dab1 we have identified a role for Dab1 after birth. The postnatal development of the cerebellum is aberrant in the absence of Dab1. Employing the hypomorphic and conditional alleles for Dab1, we will examine if Dab1 is required for adult nervous system functions, such as learning and memory, and we will examine whether genetic interactions between Dab1 and APP influence degeneration in a mouse model of Alzheimer?s disease.