Motor nerves play the critical role of shunting information out of the central nervous system to targets in the periphery. Their formation requires the coordinated development of distinct cellular components, including motor axons and the glial cells that ensheathe them. During nervous system construction, these cells must migrate long distances and coordinate their differentiation, ensuring the efficient propagation of electrical information. To better understand, diagnose and treat the many degenerative disorders of the peripheral nervous system, we need to comprehend the cellular and molecular mechanisms that mediate glial interactions along developing nerves and myelin maintenance in juvenile and adult organisms. Zebrafish provide a unique opportunity to directly observe and manipulate cell populations to gain insight into how the PNS is initially established, maintained and behaves during disease. In preliminary studies, we demonstrate that perineurial cells, which form the perineurium, originate as glial cells in the ventral spinal cord, influence Schwann cell development and are essential to motor nerve development. Therefore, in Aim 1 of this project, we will investigate the hypothesis that Schwann cells and perineurial glia reciprocally interact during nerve assembly by utilizing time-lapse imaging and genetic manipulation.
In Aim 2, we will characterize two new mutant lines that have defects in perineurial glial development and identify the mutated genes responsible for the phenotypes. Identifying these genes will give us additional information about the molecular mechanisms necessary for PNS formation. Completion of these aims will greatly expand our knowledge of the cellular and molecular mechanisms that mediate peripheral nerve development, facilitating new drug therapies intended to treat peripheral neuropathies.

Public Health Relevance

One or more damaged or dysfunctional components of peripheral nerves can result in peripheral disease or injury. Although the progression of each disorder is unique, the ultimate outcome is a greatly reduced quality of life for the afflicted individual. In this project, we will identify new cellular behaviors and novel genes that are necessary for peripheral nerve assembly and maintenance.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS072212-05
Application #
8696894
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Lewis, Gwendolyn M; Kucenas, Sarah (2014) Perineurial glia are essential for motor axon regrowth following nerve injury. J Neurosci 34:12762-77
Smith, Cody J; Morris, Angela D; Welsh, Taylor G et al. (2014) Contact-mediated inhibition between oligodendrocyte progenitor cells and motor exit point glia establishes the spinal cord transition zone. PLoS Biol 12:e1001961
Clark, Jessica K; O'keefe, Ashley; Mastracci, Teresa L et al. (2014) Mammalian Nkx2.2+ perineurial glia are essential for motor nerve development. Dev Dyn 243:1116-29
Binari, Laura A; Lewis, Gwendolyn M; Kucenas, Sarah (2013) Perineurial glia require Notch signaling during motor nerve development but not regeneration. J Neurosci 33:4241-52