Wednesday, January 15, 2025
1/15/2025
Abstract Myelination of axons in the nervous system is critical for not only conduction of action potentials, but also for providing tropic support to ensure long term survival of neurons in both the central and peripheral nervous systems. Myelin disorders are a major cause of neurological disease, and can be caused by genetic disorders, infectious disease, and inflammation. The peripheral nervous system has substantial plasticity in being able to regenerate after nerve injury, and critical transcription factors and their target gene networks have begun to be elucidated. Schwann cell reprogramming to a new differentiated state is a critical and rate limiting factor in peripheral nerve regeneration, particularly when regeneration is impaired as a function of aging/chronic denervation. Therefore, understanding the pathways that control gene expression reprogramming will provide insight into means by which remyelination after nerve injury can be accelerated. The long term objective of our laboratory is to elucidate an integrated mechanism of Schwann cell reprogramming after nerve injury based on critical transcriptional and epigenomic switches. We have found that many critical injury genes are associated with polycomb-associated histone modifications (H3K27me3 and H2AK119ub) prior to injury, and this proposal focuses on testing how reversal of the polycomb pathway is required for Schwann cell responses to peripheral nerve injury. We have also found an expected role of polycomb eraser proteins in myelin homeostasis. Using a variety of techniques established in our laboratory, we will test for the first time the involvement of modulating PRC1 pathway in nerve injury responses. In addition, our work has highlighted mechanisms by which Sonic Hedgehog is activated in repair Schwann cells, and we will employ novel mouse resources to elucidate the mechanisms and role of Sonic Hedgehog signaling in injured peripheral nerve.
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