Endothelin signaling in neural stem cell homeostasis and remyelination

PROJECT ABSTRACT Endogenous neural stem cells play a crucial role in neurogenesis and gliogenesis in the adult healthy brain and following injury or disease. In response to demyelination, or the loss of myelin sheaths surrounding axons, endogenous neural stem cells contribute to repair by upregulating gliogenesis and differentiating into myelinating oligodendrocytes. However, there is a gap in our current understanding of the mechanisms regulating adult neural stem cell-mediated remyelination. In particular, it remains unclear how neurovascular interactions within the stem cell niche respond to demyelination, and how this shapes neural stem cell behavior. We previously identified Endothelin-1 as a novel regulator of neural stem cells during development. In the adult brain, we find that endothelial cell-derived Endothelin-1 signals to neural stem cells as part of the neurovascular unit. Loss of this signaling pathway promotes gliogenesis from quiescent neural stem cells. Therefore, we hypothesize that Endothelin-1 signaling maintains adult neural stem cell quiescence, preventing differentiation in both the healthy and demyelinated brain. We will test this hypothesis through the following specific aims: In aim 1, we will use conditional knockout mice and primary cell culture to determine if Endothelin-1 signaling regulates neural stem cell quiescence in the healthy adult mouse brain. In aim 2, we will use knockout mice and the cuprizone toxicity demyelination mouse model to determine the role of Endothelin-1 signaling in neural stem cell-derived remyelination. Overall, these results will provide critical insight into the mechanism of Endothelin-1 signaling in adult neural stem cells and the feasibility of targeting this pathway to enhance remyelination.