A fundamental principle underlying this grant is that connexin 32 (Cx32) is required for normal function of Schwann cells. Though mutations in Cx32 cause alterations in channel function and are clearly associated with the X-Linked Charcot-Marie-Tooth Disease (CMTX), the pathogenesis of this disorder remains to be elucidated. The localization of Cx32 to the paranodes and Schmidt-Lantermann incisures of the myelinating Schwann cell has lead to the hypothesis that Cx32 forms reflexive gap junctions within noncompact myelin and provides a """"""""short circuit"""""""" pathway between the ab- and adaxonal cytoplasm of the myelinating Schwann cell. However, data suggest that: 1) mice lacking Cx32 show reduced capacity for regeneration associated myelination; 2) Cx32 is expressed and regulated in cultures of primary Schwann cells; 3) Schwann cells expressing two different mutant forms of Cx32 have strikingly different effects on regeneration in a xenograft model and 4) Schwann cells cultured from Cx32 knockout mice show increased death. These findings lead to the hypothesis that Cx32 is required for normal function of non-myelin-associated Schwann cells, especially those that are proliferating in response to nerve injury and participating in nerve regeneration.
Aim 1 will use morphometry, whole animal electrophysiology and behavioral and biochemical assessments to examine the hypothesis that loss of Cx32 is detrimental to normal regenerative Capacity.
Aim 2 will use Schwann cell culture and the dual patch clamp technique to examine the hypothesis that: 1) Cx32 is functionally expressed in proliferating adult Schwann cells in primary culture; 2) its expression levels are regulated by GGF (which is thought to induce Schwann cell proliferation during Wallerian degeneration); and 3) loss of Cx32 mediated cell-cell channels leads to increased Schwann cell death.
Aim 3 will use primary Schwann cells in culture and the nerve transection model to examine the hypotheses that expression of Cx32 is required to prevent apoptotic cell death and/or limit proliferation of Schwann cells. The experiments outlined in this proposal should play a key role in understanding the role of Cx32 in the Schwann cell and how mutations in Cx32 lead to inherited peripheral neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS050705-01A1
Application #
6969847
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2005-08-15
Project End
2010-05-31
Budget Start
2005-08-15
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$296,231
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Freidin, Mona; Asche-Godin, Samantha; Abrams, Charles K (2015) Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves. Exp Neurol 263:339-49
Abrams, Charles K; Islam, Mahee; Mahmoud, Rola et al. (2013) Functional requirement for a highly conserved charged residue at position 75 in the gap junction protein connexin 32. J Biol Chem 288:3609-19
Abrams, Charles K; Scherer, Steven S (2012) Gap junctions in inherited human disorders of the central nervous system. Biochim Biophys Acta 1818:2030-47
Wasseff, Sameh; Abrams, Charles K; Scherer, Steven S (2010) A dominant connexin43 mutant does not have dominant effects on gap junction coupling in astrocytes. Neuron Glia Biol 6:213-23
Freidin, Mona; Asche, Samantha; Bargiello, Thaddeus A et al. (2009) Connexin 32 increases the proliferative response of Schwann cells to neuregulin-1 (Nrg1). Proc Natl Acad Sci U S A 106:3567-72
Orthmann-Murphy, Jennifer L; Salsano, Ettore; Abrams, Charles K et al. (2009) Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 132:426-38
Orthmann-Murphy, Jennifer L; Abrams, Charles K; Scherer, Steven S (2008) Gap junctions couple astrocytes and oligodendrocytes. J Mol Neurosci 35:101-16
Sargiannidou, Irene; Ahn, Meejin; Enriquez, Alan D et al. (2008) Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants. Neurobiol Dis 30:221-33
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

Showing the most recent 10 out of 11 publications