Deciphering the cellular roles of LIS1 in the mature nervous system

摘要 LIS1 突变会对人类大脑发育产生重大病理影响，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， 分子马达对于将细胞器分配到细胞中的特定区域至关重要。 成熟神经系统中的神经元具有极长的连接，称为轴突， 对动力蛋白等运输马达的巨大需求。成年小鼠的 LIS1 缺失会导致严重的 后果——小鼠迅速出现神经系统问题，随后死亡。我们怀疑 这些严重反应是由于感觉运动和心肺回路中 LIS1 缺失引起的。 没有检测到细胞损失或神经变性，因此我们认为问题出现在 突触水平，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， 重点关注动力蛋白马达、突触和线粒体（一种重要的动力蛋白货物）。目标 2 我们建议专门从神经元（目标 2A）和一种称为胶质细胞的神经胶质细胞中去除 LIS1 星形胶质细胞（目标 2B）。两种细胞类型都表达高水平的 LIS1，并且都有助于正常细胞 突触功能。我们将能够确定这两者是否是严重疾病的细胞来源 早期小鼠模型中的症状，或者是否存在细胞类型特异性症状。 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 场。这项工作将为成人大脑中 LIS1 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.