MOLECULAR MECHANISMS THAT CONTROL NEURONAL POSITIONING

许多儿科神经疾病是由影响大脑结构形成的发育异常引起的。大脑结构在一定程度上是由神经元在大脑严格限定的区域中的精确定位决定的。在人类和其他哺乳动物中，现在已经知道了许多调控这一过程的基因。这些基因产物可能共同作用，在发育过程中调节神经元的迁移。我们感兴趣的是一组决定大脑皮层、海马体和小脑中神经层位置的基因。迁移的神经元对大脑离散区域产生的Reln蛋白做出反应，这是神经元正确定位所必需的。神经元上的受体，VLDLR或ApoER2，以及细胞内信号蛋白，如Dab1，是对Reln的适当反应所必需的。为了确定这些调控分子的作用，我们使用小鼠遗传学来分析这些基因突变时的大脑发育。例如，无论小鼠是否含有完全阻止Dab1蛋白表达的突变，或者如果它们只产生无法被酪氨酸磷酸化的Dab1突变形式，它们都具有相同的表型。这表明Dab1的酪氨酸磷酸化是神经元对Reln做出反应所必需的。我们正在努力了解这些信号分子如何调节神经元的位置，并识别迁移中的神经元对环境做出反应所需的其他基因产物。

A number of pediatric neurological disorders are caused by developmental anomalies that influence brain structure formation. The brain architecture is determined, in part, by the precise positioning of neurons in tightly defined regions of the brain. A number of genes that regulate this process are now known in humans and other mammals. These gene products likely work together to regulate the migration of neurons during development. We are interested in a group of these genes that determine the positioning of neuronal laminae in the cerebral cortex, hippocampus, and cerebellum. Migrating neurons respond to the Reln protein that is produced in discrete zones of the brain and is required for proper positioning of neurons. Receptors on neurons, VLDLR or ApoER2, and intracellular signaling proteins, such as Dab1, are required for the appropriate response to Reln. To determine the roles of these regulatory molecules we employ mouse genetics to analyze brain development when these genes are mutated. For instance, mice have the same phenotype whether they harbor a mutation that prevents Dab1 protein expression completely, or if they only produce a mutant form of Dab1 that fails to be tyrosine phosphorylated. This suggests that the tyrosine phosphorylation of Dab1 is required for neurons to respond to Reln. We are working towards an understanding of how these signaling molecules regulate neuronal positioning and the identification of other gene products that migrating neurons require to respond to their environment.