Neuron-glia interactions play a critical role during the formation of the central nervous system. Glial cells provide the pathway for the migration of postmitotic neurons away from the germinal layers. Neurons influence the proliferation, survival and differentiation of glial cells. A variety of studies have demonstrated that glia and neuronal-derived factors play critical roles in neuronal and glia precursor proliferation and differentiation, but information abut the nature of these signals remains scarce. The long range objective of the proposed research is to understand the molecular mechanisms controlling neuron-glia interactions in the developing mammalian brain. We are studying a new family of growth factors, the neuregulins, which appears to be implicated in mediating neuron- glia interactions in the peripheral and central nervous system. We now have evidence suggesting that neuregulins may play a role in neuron-glia interactions in the developing cerebellum. We have shown that neuregulin receptors, erbB4, is expressed in the radial glial fibers over which these neurons migrate. The expression of these molecules is developmentally regulated, and restricted to the period of granule cell migration. We have also demonstrated that 1) cerebellar astroglia in culture express erbB4, 2) glial erbB4 expression is regulated by extracellular signals, and 3) glial cells response to neuregulin stimulation in the same manner they respond to contact with neurons. These observations suggest that neuregulin may mediate interactions between granule cells and Bergmann glia, and that these interactions may be important for granule cell migration. The work proposed here is directed to elucidate the regulation and functions of neuregulines in the developing central nervous system.
The specific aims of the proposed research are: 1) To identify signals cells that regulate the expression of erbB receptors in cerebellar astroglial cells; 2) To determine effects of NRG on Bergmann glial cell biology, and to determine the contribution of NRG to the effects of granule neurons on the glial cells; 3) To determine the role of NRG in granule cell migration. We will study the role of neuregulin in cerebellar granule cell - Bergamann glia interactions in vitro using cellular and molecular techniques. Neuregulin receptors have a wide range of normal biological actions, but are also proto-oncogenes. Therefore, it is likely that alteractions in the function or expression of either ligand or receptors, will be involved in developmental processes that lead to cancer, mental retardation, epilepsy and other central and peripheral nervous system diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS035884-01A1
Application #
2389645
Study Section
Neurology C Study Section (NEUC)
Program Officer
Leblanc, Gabrielle G
Project Start
1997-07-28
Project End
2000-05-31
Budget Start
1997-07-28
Budget End
1998-05-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Rao, Meenakshi; Rastelli, Daniella; Dong, Lauren et al. (2017) Enteric Glia Regulate Gastrointestinal Motility but Are Not Required for Maintenance of the Epithelium in Mice. Gastroenterology 153:1068-1081.e7
Rao, Meenakshi; Nelms, Bradlee D; Dong, Lauren et al. (2015) Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system. Glia 63:2040-2057
Giera, Stefanie; Deng, Yiyu; Luo, Rong et al. (2015) The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat Commun 6:6121
Hedstrom, Kristian L; Murtie, Joshua C; Albers, Kathryn et al. (2014) Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFR?/RET receptor signaling. Proc Natl Acad Sci U S A 111:2325-30
Long, Patrick; Corfas, Gabriel (2014) Dynamic regulation of myelination in health and disease. JAMA Psychiatry 71:1296-7
Long, Patrick; Corfas, Gabriel (2014) Neuroscience. To learn is to myelinate. Science 346:298-9
Song, Sungmin; Rosen, Kenneth M; Corfas, Gabriel (2013) Biological function of nuclear receptor tyrosine kinase action. Cold Spring Harb Perspect Biol 5:
Xu, Pin; Rosen, Kenneth M; Hedstrom, Kristian et al. (2013) Nerve injury induces glial cell line-derived neurotrophic factor (GDNF) expression in Schwann cells through purinergic signaling and the PKC-PKD pathway. Glia 61:1029-40
Zilberstein, Yael; Liberman, M Charles; Corfas, Gabriel (2012) Inner hair cells are not required for survival of spiral ganglion neurons in the adult cochlea. J Neurosci 32:405-10
Makinodan, Manabu; Rosen, Kenneth M; Ito, Susumu et al. (2012) A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 337:1357-60

Showing the most recent 10 out of 44 publications