Molecular Mechanisms That Control Neuronal Positioning D

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。使用果蝇的遗传测试，我们证明了淀粉样前体蛋白（APP）家族成员和小鼠Dab 1之间的拮抗作用。 我们最近测试了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，APP基因，这是参与阿尔茨海默氏症？这种疾病会影响控制大脑发育的分子通路。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。 我们已经产生了一个条件等位基因Dab 1，并利用这一点来了解Dab 1在小脑的出生后发育的作用。特别是，我们感兴趣的浦肯野细胞，这需要Dab 1迁移在胚胎发育过程中，需要Dab 1在出生后在不断扩大的小脑重新定位。为了研究这一点，我们将在出生后的不同时间检测Dab 1基因，并检查这些动物的小脑是否有任何浦肯野细胞异位。

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. Using a genetic test in Drosophila we demonstrated antagonism between the amyloid precursor protein (APP) family members and mouse Dab1. We have recently tested for 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 Alzheimer?s 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 generated a conditional allele for Dab1 and are using this to understand the role of Dab1 in the postnatal development of the cerebellum. In particular we are interested in whether Purkinje cells, which require Dab1 for migration during embryogenesis, require Dab1 during repositioning in the expanding cerebellum after birth. To investigate this we will inactivate the Dab1 gene at various times after birth and examine the cerebella of these animals for any Purkinje cell ectopias.