Abstract

Myelination of the central nervous system (CNS) by oligodendrocytes (OLs) is essential for the development and function of the CNS. Myelin develops in the CNS as OLs differentiate into the myelin-forming mature phenotype. The differentiation of OLs is under tight regulation, and its dysregulation causes neurological disorders and has been linked to neuropsychiatric diseases. Genetic studies have shown that Myrf is a key transcription factor for the development and life-long maintenance of myelin in the CNS. Recent studies have also demonstrated that Myrf is critical to the fine-tuning of myelin thickness and its plasticity that underlies learning in the adult stage. Despite these crucial role, it remains poorly understood how Myrf regulates transcription, and this significantly impedes the progress in this field. Using bioinformatics and experimental approaches, we recently made the breakthrough observations that Myrf is a membrane-bound transcription factor, and that Myrf may function as a homo-trimeric transcription factor. Membrane-bound transcription factors are generated as membrane proteins that, upon relevant stimuli, undergo proteolytic activation to release transcription factor domains from the membrane, with Notch being the most famous example. Our discovery fundamentally changes the paradigm for Myrf, providing a powerful framework to understand its functional mechanism. Building upon this discovery, Aim I will elucidate how Myrf is activated by proteolysis. The proteolytic activation of Myrf releases its N-terminal fragment from the membrane, allowing it to translocate into the nucleus for transcriptional regulation.
Aim II will determine how the N-terminal fragment of Myrf interacts with DNA as a homo-trimer for transcription. Our computational and experimental analyses indicate that functional collaboration with other transcription factors is critical to the transcriptional activity of Myrf.
Aim III will elucidate which transcription factors interact with yrf for coordinated differentiation of OLs. In sum, this study will elucidate the transcription mechanism of Myrf for OL differentiation and CNS myelination.

Public Health Relevance

Myelination of the central nervous system by oligodendrocytes is essential for the development and function of the central nervous system. Impaired myelination causes neurological disorders and has also been linked to neuropsychiatric diseases. This project will elucidate the mechanism of action of Myrf, a key transcription factor for central nervous system myelination.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094181-04
Application #
9526034
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2015-09-15
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
State University of New York at Buffalo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228