Mutations in GJB1, GJA1, and GJA12, the genes that encode human connexin32 (hCx32), hCx43, and hGx47, cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), oculodehtodigital. dysplasia (ODDD), and PeHzaeus-Merzbacher-ijke disease (PMLD), respectively, all of which cause important CNS abnormalities that appear to be related to abnormal functioning of oligodendrocytes. The central theme of this grant is that Cx30:Cx32 and Cx43:Cx47 heterptypic channels mediate astrocyte/oligodendrocyte (A/O) coupling, which is disrupted by mutations of GJB1/Cx32,GJA1/Cx43, or GJA12/Cx47. 1.Investigate the molecular defects of hCx47 mutants causingi PMLD. We will characterize further the nature.ofthese defects, .arid determine whether wild type (WT) hCx47 or these hOx47 mutants can form functional channels with hCx43 by dye transfer and electrophysiblogy. 2. Investigate the molecular defects of hCx43 jmytants causing ODDD. We will investigate the molecular nature of the mutaiit proteins, determine whether cells expressing an ODDD mutant can form functional channels by themselves, or with celJs expressing either WT hCx43 or WT iGx47, and determine.1whether ODDD mutants'have dominant-negative effects on-WT hCx43. 3-Determine whether hCx32 """"""""CNS mutants"""""""" have dominant effects on hCx47. ? ,.'..' n HeLa cells these """"""""CNS mutants"""""""" accumulatefiithef in.the endoplasniic reticujum (ER) or in the Gblgi. Our Dreliminary evidenceindicates that co-expression of these.""""""""CNS mutants"""""""" with WT hCx47 results in partial retention of Wt hCx47 in the ER or Golgi, indicating .tn.atthese Cx32 mutants exert a dominant effect on WT hCx47. We will characterize further the nature of these defects. . . 4. Determine the role of Cx32 and Cx47 in astrocyte/oligodendrocyte coupling. We will immunostain the brains of mice that lack Cx32 and/or Cx47, and determine whether the localization of their proposed partners is altered. We will also investigate A/O coupling by injecting astrpcytes genetically abeled with green fluorescent protein (GFP) in acute spinal cord slices from Gjb1/cx32 and Gja12/cx47 double hull"""""""" mice with small molecules that can cross GJs. In this way, we will determine the relative mportance of the two kinds of heterotypic channels in A/0 coupling.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-J (02))
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Porter, John D
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University of Pennsylvania
Schools of Medicine
United States
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Wasseff, Sameh K; Scherer, Steven S (2015) Activated immune response in an inherited leukodystrophy disease caused by the loss of oligodendrocyte gap junctions. Neurobiol Dis 82:86-98
Wasseff, Sameh K; Scherer, Steven S (2014) Activated microglia do not form functional gap junctions in vivo. J Neuroimmunol 269:90-3
Abrams, Charles K; Scherer, Steven S; Flores-Obando, Rafael et al. (2014) A new mutation in GJC2 associated with subclinical leukodystrophy. J Neurol 261:1929-38
Kleopa, Kleopas A; Abrams, Charles K; Scherer, Steven S (2012) How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease? Brain Res 1487:198-205
Abrams, Charles K; Scherer, Steven S (2012) Gap junctions in inherited human disorders of the central nervous system. Biochim Biophys Acta 1818:2030-47
Ferguson, Toby A; Scherer, Steven S (2012) Neuronal cadherin (NCAD) increases sensory neurite formation and outgrowth on astrocytes. Neurosci Lett 522:108-12
Scherer, Steven S; Kleopa, Kleopas A (2012) X-linked Charcot-Marie-Tooth disease. J Peripher Nerv Syst 17 Suppl 3:9-13
Zhang, Junxian; Scherer, Steven S; Yum, Sabrina W (2011) Dominant Cx26 mutants associated with hearing loss have dominant-negative effects on wild type Cx26. Mol Cell Neurosci 47:71-8
Holzbaur, Erika L F; Scherer, Steven S (2011) Microtubules, axonal transport, and neuropathy. N Engl J Med 365:2330-2
Wasseff, Sameh K; Scherer, Steven S (2011) Cx32 and Cx47 mediate oligodendrocyte:astrocyte and oligodendrocyte:oligodendrocyte gap junction coupling. Neurobiol Dis 42:506-13

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