L-type Calcium Channel Regulation of Neuronal Differentiation

描述（由申请人提供）：l型电压门控钙通道（LTCs）突变与自闭症和其他神经发育障碍有关。本项目旨在研究LTCs如何调节神经祖细胞（NPC）的增殖和分化。神经发育涉及一系列协调的事件，这些事件平衡了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。像CaV1.2这样的LTCs将电信号转化为钙信号，控制生化途径并激活发育中的神经系统的基因表达程序。CaV1.2功能突变的增加导致Timothy综合征（TS），这是一种以自闭症和智力迟钝为特征的多系统疾病。我们实验室已经生成了TS的转基因小鼠模型，我发现这些动物的心室区（VZ）的npc增殖显著增加。使用体外系统研究神经元分化，我还发现，过度表达含有TS突变的野生型CaV1.2或CaV1.2 （TS-CaV1.2）会导致神经元分化的严重损害。此外，阻断内源性LTCs也会减少体外鼻咽癌的分化。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迟钝的潜在病理生理学提供新的见解。

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.