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位置迁移到它们整合成功能网络的区域。已经确定了许多调节离散迁移事件的基因。神经元迁移失败可导致从癫痫到智力迟钝等严重疾病。

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.