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.
