Deciphering the cellular roles of LIS1 in the mature nervous system

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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.