Abstract

The long-term goal of this project is to understand how oligodendrocytes, the myelinating glial cells of the central nervous system (CNS), are produced. During development, dividing neuroepithelial precursors give rise to oligodendrocyte progenitor cells (OPCs). Following migration to become dispersed throughout the CNS, some OPCs differentiate as myelinating oligodendrocytes but others remain in a non-myelinating state into adulthood. The mechanisms that guide formation of OPCs from proliferating neuroepithelial precursors and specify myelinating and non-myelinating fates are not well known. Using zebrafish as a model system, this project combines in vivo live cell imaging with genetic and pharmacological manipulations to test novel hypotheses formulated to identify mechanisms that regulate OPC specification.
Specific Aim 1 will test the hypothesis that microRNA inhibition of apical Par polarity proteins regulates the proliferation to differentiation transition by making precursors less sensitive to Shh signaling.
Specific Aim 2 will test the hypothesis that different levels of Shh signaling specify myelinating and non-myelinating OPCs.
Specific Aim 3 will identify gene functions that mediate specification of myelinating and non-myelinating OPC fates in response to differential Shh signaling. Completion of these Aims will fill important gaps in our basic knowledge of neural development and reveal molecular targets that could be used to promote myelination following injury or disease.

Public Health Relevance

Precisely controlled formation of myelin on central nervous system axons is essential for motor and intellectual function. The long term goal of this project i to understand how neural precursors produce oligodendrocytes, which are the myelinating glial cells of the central nervous system. Completion of the project aims will substantially extend our understanding of the molecular mechanisms by which sufficient numbers of oligodendrocytes are produced to create the myelin necessary for brain function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046668-13
Application #
9248450
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (02)M)
Program Officer
Morris, Jill A
Project Start
2003-07-01
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
13
Fiscal Year
2017
Total Cost
$306,140
Indirect Cost
$109,265

  Institution

Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Ravanelli, Andrew M; Kearns, Christina A; Powers, Rani K et al. (2018) Sequential specification of oligodendrocyte lineage cells by distinct levels of Hedgehog and Notch signaling. Dev Biol 444:93-106
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
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
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
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

Showing the most recent 10 out of 27 publications