Deciphering the cellular roles of LIS1 in the mature nervous system

摘要 Lis1突变可能会对人类大脑发育产生重大的病理影响，但我们有 对LIS1的发育后作用只有最低限度的了解。Lis1调节动力蛋白，a 分子马达，对于将细胞器分布到细胞中的特定区域至关重要。 成熟神经系统中的神经元有非常长的连接，称为轴突，位于 对像动力系统这样的运输马达的巨大需求。成年小鼠的Lis1耗尽严重 后果--小鼠迅速出现神经系统问题，随后死亡。我们怀疑 这些严重的反应是由感觉运动和心肺循环中的LIS1缺失引起的。 没有检测到细胞丢失或神经变性，所以我们认为问题出现在 突触的水平，这是对正常电路至关重要的特殊结构。在目标1中，我们将 确定与病理反应相关的分子和细胞变化， 专注于动力蛋白发动机、突触和线粒体，这是一种重要的动力蛋白物质。在AIM 2 我们建议从神经元(Aim 2A)和一种称为AN的神经胶质细胞中特异性地去除Lis1 星形胶质细胞(目标2B)。这两种细胞都表达高水平的Lis1，并且都有助于正常 突触功能。我们将能够确定这两种病毒中的任何一种是否是严重的 早期小鼠模型中的症状，或者如果有细胞类型特定的症状。LIS1有一个 已知在轴突运输中的作用，但其在成熟星形胶质细胞中的功能在 菲尔德。这项工作将为理解Lis1在成人大脑中的功能带来新的见解。

SUMMARY LIS1 mutations can have major pathological effects on human brain development, but we have only a minimal understanding of the postdevelopmental roles of LIS1. LIS1 regulates dynein, a molecular motor that is vitally important for distributing organelles to specific regions in the cell. Neurons in the mature nervous system have extremely long connections called axons that place huge demands on transport motors like dynein. LIS1 depletion in adult mice has severe consequences - mice rapidly develop neurological problems followed by death. We suspect that these severe responses are caused by LIS1 loss in sensorimotor and cardiorespiratory circuits. There was no detectable cell loss or nerve degeneration so we think the problems arise at the level of the synapses, specialized structures that are critical for normal circuits. In Aim 1 we will determine the molecular and cellular changes correlated with the pathological responses, focusing on dynein motors, synapses, and mitochondria, an important dynein cargo. In Aim 2 we propose to deplete LIS1 specifically from neurons (Aim 2A) and a type of glial cell called an astrocyte (Aim 2B). Both cell types express high levels of LIS1, and both contribute to normal synaptic function. We will be able to determine if either are the cellular source of the severe symptoms in the earlier mouse model, or if there are cell type specific symptoms. LIS1 has a known role in axon transport but its function in mature astrocytes has been overlooked in the field. This work will bring new insight into functions of LIS1 in the adult brain.