The long term goal of this project is to understand how oligodendrocytes, the cells responsible for making the myelin that insulates axons in the central nervous system, arise from neural precursor cells. During development, rapidly dividing neural precursors produce first neurons and then oligodendrocytes. This process must be tightly regulated to ensure that sufficient numbers of oligodendrocytes are produced and to prevent neural precursors from dividing too much. Using zebrafish as a model system, this project combines in vivo time-lapse imaging and genetic analysis to investigate genes that are necessary to regulate formation of oligodendrocytes from neural precursors. In previous studies, we performed a screen for newly induced mutations that disrupt the number and distribution of oligodendrocytes, began to characterize how these mutations affect oligodendrocyte development and identified some of the mutated genes. During the new project period we will extend our investigation of neural precursor maintenance and oligodendrocyte specification by using time-lapse imaging and genetic analysis to test the roles of cell division orientation and Notch signaling in regulating formation of neural cell lineages.
Specific Aim 1 will analyze neural precursor division patterns during neurogenesis and gliogenesis and test the requirement of atypical Protein Kinase C in maintaining self-renewing precursor divisions.
Specific Aim 2 will investigate the role of Notch signaling in promoting oligodendrocyte specification.
Specific Aim 3 will investigate the function of Fbw7, the recognition subunit of an E3 SCF ubiquitin ligase, and test the hypothesis the Fbw7 regulates oligodendrocyte specification by modulating Notch activity. Completion of these aims will greatly extend our understanding of the molecular mechanisms that maintain neural precursors and guide oligodendrocyte formation, facilitating effective design of therapies intended to treat developmental and degenerative myelin disease and nervous system injury.

Public Health Relevance

Failure to form or maintain myelin, the insulation that permits rapid transmission of nerve impulses, results in profound neurological deficits. This project seeks to identify the genes required for formation of myelinating cells in the developing nervous system, which could enhance the design of therapies to promote myelination and remyelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046668-08
Application #
8206567
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Morris, Jill A
Project Start
2003-07-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$327,994
Indirect Cost
$113,619
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Hughes, Ethan G; Appel, Bruce (2016) The cell biology of CNS myelination. Curr Opin Neurobiol 39:93-100
Hudish, Laura I; Galati, Domenico F; Ravanelli, Andrew M et al. (2016) miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling. Development 143:2292-304
Hines, Jacob H; Ravanelli, Andrew M; Schwindt, Rani et al. (2015) Neuronal activity biases axon selection for myelination in vivo. Nat Neurosci 18:683-9
Yang, Michele L; Shin, Jimann; Kearns, Christina A et al. (2015) CNS myelination requires cytoplasmic dynein function. Dev Dyn 244:134-45
Ravanelli, Andrew M; Appel, Bruce (2015) Motor neurons and oligodendrocytes arise from distinct cell lineages by progenitor recruitment. Genes Dev 29:2504-15
Kearns, Christina A; Ravanelli, Andrew M; Cooper, Kirsten et al. (2015) Fbxw7 Limits Myelination by Inhibiting mTOR Signaling. J Neurosci 35:14861-71
Mathews, Emily S; Mawdsley, David J; Walker, Macie et al. (2014) Mutation of 3-hydroxy-3-methylglutaryl CoA synthase I reveals requirements for isoprenoid and cholesterol synthesis in oligodendrocyte migration arrest, axon wrapping, and myelin gene expression. J Neurosci 34:3402-12
Hudish, Laura I; Blasky, Alex J; Appel, Bruce (2013) miR-219 regulates neural precursor differentiation by direct inhibition of apical par polarity proteins. Dev Cell 27:387-98
Snyder, Julia L; Kearns, Christina A; Appel, Bruce (2012) Fbxw7 regulates Notch to control specification of neural precursors for oligodendrocyte fate. Neural Dev 7:15
Zannino, Denise A; Sagerstrom, Charles G; Appel, Bruce (2012) olig2-Expressing hindbrain cells are required for migrating facial motor neurons. Dev Dyn 241:315-26

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