A novel role for cell cycle regulators in oligodendrogenesis and myelination

Myelination of axons by oligodendrocytes is critical for proper central nervous system function. The transition from oligodendrocyte precursor cells (OPCs) to mature, myelinating oligodendrocytes is tightly regulated, but the molecular mechanisms governing this process remain poorly understood. This proposal aims to elucidate the role of Cyclin Y-like 1 (CCNYL1) in oligodendrocyte differentiation and myelination. Building on preliminary data demonstrating CCNYL1's crucial role in oligodendrocyte differentiation in zebrafish, this research aims to elucidate the molecular mechanisms governing these processes through three specific aims: 1) define CCNYL1's role in developmental oligodendrogenesis using zebrafish and mouse models, 2) investigate pathways regulated by CCNYL1 in differentiating oligodendrocytes with a focus on Wnt signaling, and 3) determine CCNYL1's influence on experience-dependent myelination and remyelination in adult mice.

This research employs cutting-edge techniques including in vivo imaging, CRISPR-mediated gene editing, proteomics, and behavioral studies, with the ability to uncover novel molecular pathways controlling oligodendrocyte formation. Understanding these processes is essential for developing targeted therapies for demyelinating diseases like multiple sclerosis, where impaired oligodendrocyte differentiation contributes to remyelination failure. By elucidating CCNYL1's role in oligodendrocyte biology across different contexts—from development to adulthood and in disease states—this work may uncover novel therapeutic targets to enhance myelination and promote repair in the central nervous system. This research will take place at OHSU’s Vollum Institute, a hotspot of glial biologists and myelin researchers, including Drs.

Kelly Monk, Ben Emery, and Marc Freeman, who will all advise the progress of this research and provide support and training in biochemistry and proteomics. OHSU’s state of the art equipment and core facilities will streamline the proposed experiments and provide crucial technical support in experimental design and analysis. During the training period, the applicant will master rigorous experimental design and statistical analysis and develop skills in mentorship, teaching, and lab management with an emphasis on supporting underrepresented groups in science. This comprehensive career development plan, combined with the candidate's strong background and supportive mentoring team, positions the applicant well for a successful transition to independence as a faculty member leading a research program in glial cell biology and neuroscience.

Grant Number: 1K99NS144382-01
NIH Institute/Center: NIH
Principal Investigator: Cody Call