L-type Calcium Channel Regulation of Neuronal Differentiation

L型电压门控钙通道（LTC）的突变与自闭症和其他神经发育障碍有关。本课题的目的是研究LTC对神经祖细胞增殖和分化的调控作用。神经发育涉及一系列协调事件，其平衡NPC的维持和增殖与子细胞的分化以产生构成成熟大脑皮层的神经元群体。LTC如CaV1.2将电信号转化为钙信号，控制生物化学途径并激活发育中神经系统的基因表达程序。CaV1.2的功能突变的获得导致提摩太综合征（Timothy Syndrome，TS），一种以自闭症和精神发育迟滞为特征的多系统疾病。我们的实验室已经产生了一个转基因小鼠模型TS和我已经发现，有一个显着的增加，在这些动物的心室区（VZ）的NPC的增殖。使用体外系统研究神经元分化，我还发现过表达野生型CaV 1.2或含有TS突变的CaV 1.2（TS-CaV 1.2）导致神经元分化的显著损害。此外，阻断内源性LTC也降低了体外NPC分化。该项目的目标是通过研究发育过程中CaV1.2的调节以及这些通道在体外和体内控制NPC分化的机制来扩展这些初步发现。这些研究将扩大我们对活动如何调节大脑发育的理解，并将为自闭症和智力迟钝的潜在病理生理学提供新的见解。

Mutations in L-type voltage gated calcium channels (LTCs) are associated with autism and other neurodevelopmental disorders. The goal of this project is to investigate how LTCs regulate neural progenitor cell (NPC) proliferation and differentiation. Neural development involves a series of coordinated events that balance maintenance and proliferation of NPCs with the differentiation of daughter cells to generate the neuronal populations that comprise the mature cerebral cortex. LTCs such as CaV1.2 convert electrical signals into calcium signals that control biochemical pathways and activate programs of gene expression in the developing nervous system. A gain of function mutation in CaV1.2 leads to Timothy Syndrome (TS), a multi- systemic disorder characterized by autism and mental retardation. Our laboratory has generated a transgenic mouse model for TS and I have found that there is a significant increase in proliferation of NPCs in the ventricular zone (VZ) of these animals. Using an in vitro system to study neuronal differentiation, I have also found that over-expression of wildtype CaV1.2 or CaV1.2 containing the TS mutation (TS-CaV1.2) results in a dramatic impairment of neuronal differentiation. Furthermore, blocking endogenous LTCs also reduces NPC differentiation in vitro. The goal of this project is to extend these initial findings by investigating both the regulation of CaV1.2 during development and the mechanisms by which these channels control NPC differentiation in vitro and in vivo. These studies will expand our understanding of how activity regulates brain development and will provide new insights into the underlying pathophysiology of autism and mental retardation.