L-type Calcium Channel Regulation of Neuronal Differentiation

描述(申请人提供)：L类电压门控钙通道(LTC)的突变与自闭症和其他神经发育障碍有关。本项目的目的是研究LTCs如何调控神经前体细胞(NPC)的增殖和分化。神经发育涉及一系列协调的事件，平衡神经前体细胞的维持和增殖与子代细胞的分化，以产生组成成熟大脑皮层的神经元群。LTCs，如CaV1.2，将电信号转化为钙信号，控制生化途径，激活发育中神经系统的基因表达程序。CaV1.2功能突变的获得会导致Timothy综合征(TS)，这是一种以自闭症和智力低下为特征的多系统疾病。我们的实验室已经建立了一种转基因的TS小鼠模型，我发现这些动物的脑室区(VZ)中的NC细胞的增殖显著增加。使用体外系统研究神经元分化，我还发现，野生型CaV1.2或含有TS突变的CaV1.2(TS-CaV1.2)的过度表达会导致神经元分化的显著损害。此外，阻断内源性LTCs也可减少鼻咽癌的体外分化。该项目的目标是通过研究CaV1.2在发育过程中的调节以及这些通道在体外和体内控制鼻咽癌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低下的潜在病理生理学提供新的见解。 与公共健康相关：在美国，自闭症谱系障碍影响了100多万儿童。这里描述的研究重点是一种名为Timothy综合征的遗传性自闭症，这种自闭症是由电压门控钙通道CaV1.2突变引起的。这项工作将探索这种突变影响发育中大脑神经发生的机制，并将为可能导致Timothy综合征自闭症以及其他自闭症谱系障碍的细胞和分子机制提供见解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders affect more than a million children in the US. The research described here focuses on an inherited form of autism called Timothy Syndrome that is caused by a mutation in the voltage-gated calcium channel CaV1.2. This work will explore the mechanisms by which this mutation influences neurogenesis in the developing brain and will provide insights into cellular and molecular mechanisms that may cause autism in Timothy Syndrome, as well as other autism spectrum disorders.