Sunday, May 11, 2025
5/11/2025
Control of CNS Myelination by the E3 Ligase Component Fbxw7 - PROJECT SUMMARY Myelination in the vertebrate central nervous system (CNS) is an evolutionarily conserved process where oligodendrocytes (OLs), a glial cell type within the CNS, wrap surrounding axons in membrane sheaths providing vital trophic support and insulation. This incredibly complex and dynamic process of myelination occurs throughout life, both in response to injury and as a continuous refinement of circuit dynamics. A previous forward genetic screen in zebrafish, aimed at identifying novel regulators of myelination, identified Fbwx7 as a negative regulator of CNS myelination. Fbxw7 is a recognition subunit of the SKP1-Cullin-Fbox (SCF) ubiquitin ligase complex. Loss of Fbxw7 resulted in a significant increase in myelin basic protein (mbp) expression, the number of OL lineage cells, and an increase in the number of myelinated axons and myelin wraps in the dorsal spinal cord of zebrafish. Additionally, loss of Fbxw7 in mature myelinating OLs in the mouse optic nerve resulted in a significant increase in the density of abnormally thick myelinated axons, myelin outfoldings, and degenerating axons, showing for the first time a role for Fbxw7 in regulating myelin homeostasis in the mammalian CNS. To determine the substrates that Fbxw7 might be regulating to control CNS myelination, I silenced Fbxw7 in primary OL cultures, and found a significant increase in the levels of the transcription factor Myelin Regulator Factor (Myrf), a key protein essential for myelination, and many novel proteins. I hypothesize that Fbxw7 controls CNS myelination by degrading protein substrates that regulate OPC proliferation, differentiation, and/or OL sheath length and myelin thickness. To investigate this, I will 1) examine OL development and dynamics in Fbxw7 loss of function zebrafish mutants and in OL lineage specific Cre mouse models, and 2) determine Fbxw7 substrates that regulate OL development and myelination using zebrafish genetics and rodent culture models. By combining these approaches, I will receive training in a diverse array of experimental methods and model systems, providing me with skills and options to pursue a successful career in science. Additionally, my co-appointment in Dr. Ben Emery’s (Jungers Center for Neuroscience Research) and Dr. Kelly Monk’s (Vollum institute) laboratories will provide me with institutional support from two exemplary departments and access to a large group of diverse PIs and trainees to aid in my scientific growth and training.
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