Transcriptional control of OPC fate specification and homing to gray matter and white matter in the CNS - PROJECT SUMMARY Oligodendrocyte precursor cells (OPCs) are one the most proliferative and abundant cell types in the central nervous system (CNS). During development, OPCs widely dispersed into areas of gray matter or white matter, and readily differentiate to give rise to oligodendrocytes, which are responsible for insulating neuronal axons with myelin. Studies in mouse models have revealed that abnormal development of OPCs and oligodendrocytes is one of the underlying causes of neurological diseases and disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and glioblastoma, the deadliest of brain cancers. Currently, it is unknown how OPCs are regulated to populate the gray matter (GM) or white matter (WM), and what mechanisms are responsible for selectively maintaining many OPCs in undifferentiated state while others mature into oligodendrocytes. Prior studies demonstrate that the transcription factor, ASCL1, is differentially expressed in OPCs, where it is relatively higher in WM-OPCs than in GM-OPCs. Experiments outlined in this proposal are designed to test the overall hypothesis that the level of ASCL1 specifies the fate of OPCs and determines their homing and properties in the GM or WM. To test this hypothesis, the proposed study will pursue the following specific aims. Specific Aim 1. To determine if a sustained high level of ASCL1 is responsible for specifying OPC fate and homing to WM over GM in the brain. Specific Aim 2. To identify functionally relevant genetic targets of ASCL1 specifically in OPCs using ChIP-seq and Ribo-Tag. Specific Aim 3. To determine if Cntn1, a novel target of ASCL1 that encodes for a cell surface protein, functions downstream of ASCL1 to mediate the homing of OPCs to the WM. Both ASCL1 and CNTN1 are essential for OPC development, proper myelination, and glioma progression and metastasis. We anticipate that completion of this study will offer new mechanistic insights into how OPC/oligodendrocyte related pathological conditions such as demyelination, neuronal degeneration, and cancers arise in the CNS, while at the same time also provide an entry point to potentially manipulate these cells for the treatment of these debilitating diseases.
