? ? CNS myelination depends on the proper function of connexin32 (Cx32) and Cx47, which are gap junction proteins expressed by oligodendrocytes. Defects in the genes that encode these connexins, GJB1/Cx32 and GJA12/Cx47, cause CNS white matter tract disorders, including X-linked Charcot-Marie-Tooth Disease and Pelizaeus-Merzbacher-like Disease, respectively. Deletion of both GJB1/Cx32 and GJA12/Cx47 genes in mice results in a severe dysmyelinating phenotype and death by six weeks of age that does not occur with deletion of either gene alone, suggesting that these proteins serve overlapping functions. Anatomical and functional studies demonstrate that gap junctions couple astrocytes and oligodendrocytes, and Cx32 and Cx47 likely comprise the oligodendrocyte portion of these gap junction channels. We propose that mutations in the genes that encode Cx32 and Cx47 disrupt coupling between astrocytes and oligodendrocytes. The goal of this grant is to investigate the properties of mutant Cx32 and mutant Cx47 in the context of interactions with connexins expressed by the same cells and by apposing cells. This work should elucidate the molecular composition of gap junction channels that couple astrocytes and oligodendrocytes. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30NS054363-01
Application #
7053019
Study Section
Special Emphasis Panel (ZNS1-SRB-M (24))
Program Officer
Porter, John D
Project Start
2006-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$29,193
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Orthmann-Murphy, Jennifer L; Abrams, Charles K; Scherer, Steven S (2008) Gap junctions couple astrocytes and oligodendrocytes. J Mol Neurosci 35:101-16
Orthmann-Murphy, Jennifer L; Enriquez, Alan D; Abrams, Charles K et al. (2007) Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci 34:629-41
Orthmann-Murphy, Jennifer L; Freidin, Mona; Fischer, Esther et al. (2007) Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins. J Neurosci 27:13949-57