The systematic wrapping of an axon by insulating myelin sheaths is a remarkable event in the development of the vertebrate central nervous system (CNS). Despite the importance of myelin for the rapid conduction of action potentials, little is known about its molecular mechanism. In this proposal, we will focus on understanding the transcriptional control of CNS myelination. Although several transcription factors have been identified that are required for the generation of oligodendrocytes and their precursor cells, the transcriptional mechanisms that control expression of CNS myelin genes are still poorly understood. In a recent screen for transcripts that display cell-type specific expression within the CNS, we identified an uncharacterized putative transcription factor, gene model 98 (GM98), which is expressed specifically by postmitotic oligodendrocytes (OLs). We have demonstrated that GM98 is a nuclear protein and that its mRNA and protein are highly expressed specifically by OLs, but not by OL precursor cells or other CNS cell types. In vitro, we have found that the expression of GM98 is both necessary and sufficient for oligodendrocyte progenitors to differentiate into postmitotic oligodendrocytes expressing myelin genes. In this proposal we will further characterize the role of GM98 as a transcriptional regulator in oligodendrocyte generation and myelination, identify GM98 binding partners, and investigate the genomic regions and genes that are targeted by GM98. These experiments will provide a better understanding of the molecular mechanisms that control CNS myelination. Understanding how myelination is regulated may suggest new ways of enhancing remyelination after injury or diseases such as optic neuritis and Multiple Sclerosis.

Public Health Relevance

Demyelination of CNS axons can cause failure of action potential conduction leading to devastating neurological dysfunctions in Multiple Sclerosis and other demyelinating diseases. Understanding how myelin genes are regulated may prove vital for restoring myelination in demyelinating diseases. These studies have the potential to shed new light on how myelination normally occurs and how myelin can be repaired in many different neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010257-16
Application #
8324696
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Steinmetz, Michael A
Project Start
1995-07-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
16
Fiscal Year
2012
Total Cost
$381,540
Indirect Cost
$143,940
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Zuchero, J Bradley; Fu, Meng-Meng; Sloan, Steven A et al. (2015) CNS myelin wrapping is driven by actin disassembly. Dev Cell 34:152-67
Gibson, Erin M; Purger, David; Mount, Christopher W et al. (2014) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344:1252304
Zuchero, J Bradley (2014) Purification and culture of dorsal root ganglion neurons. Cold Spring Harb Protoc 2014:813-4
Zuchero, J Bradley (2014) Purification of dorsal root ganglion neurons from rat by immunopanning. Cold Spring Harb Protoc 2014:826-38
Brosius Lutz, Amanda; Barres, Ben A (2014) Contrasting the glial response to axon injury in the central and peripheral nervous systems. Dev Cell 28:7-17
Zuchero, J Bradley; Barres, Ben A (2013) Intrinsic and extrinsic control of oligodendrocyte development. Curr Opin Neurobiol 23:914-20
Yang, Nan; Zuchero, J Bradley; Ahlenius, Henrik et al. (2013) Generation of oligodendroglial cells by direct lineage conversion. Nat Biotechnol 31:434-9
Bujalka, Helena; Koenning, Matthias; Jackson, Stacey et al. (2013) MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol 11:e1001625
Dugas, Jason C; Ibrahim, Adiljan; Barres, Ben A (2012) The T3-induced gene KLF9 regulates oligodendrocyte differentiation and myelin regeneration. Mol Cell Neurosci 50:45-57
Koenning, Matthias; Jackson, Stacey; Hay, Curtis M et al. (2012) Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci 32:12528-42

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