Previously, we showed that mutations in the gene encoding connexin32 (Cx32) caused a demyelinating peripheral neuropathy called Charcot-Marie-Tooth disease (CMTX). Consistent with this finding, Schwann cells contain Cx32 and regulate its expression like a myelin-related gene. Thus, maintenance of myelin in the human peripheral nervous system requires connexin expression. However, oligodendrocytes also express and regulate Cx32 like a myelin gene and yet central abnormalities are rare in CMTX patients. Since one explanation for this discrepancy would be redundant expression of other connexins, we searched for connexins in myelinating glia. We found two novel connexins, Cx29 and Cx47. All three connexins can be found in oligodendrocytes and Schwann cells. Cx29 and Cx32, however, are present in non-overlapping subsets of spinal cord oligodendrocytes and,while they are both present in Schwann cells, their subcellular distributions are strikingly different. Single knockouts of either Cx32 or Cx47 myelinate relatively normally and have no functional deficits. In contrast, double knockouts develop severe central demyelination and die during the 6th postnatal week of life. Surprisingly, these animals display only subtle abnormalities in peripheral myelin. Together, our studies suggest that connexins are critical for both central and peripheral myelination but that different connexins may have different functions within myelinating glia. We propose to define the separate and interacting roles of connexins in myelination using a combination of immunocytochemistry, targeted gene ablation and functional analysis of connexin channel activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM037751-18
Application #
6750027
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Shapiro, Bert I
Project Start
1986-12-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
18
Fiscal Year
2004
Total Cost
$415,275
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Hou, Mingli; Li, Yaqiao; Paul, David L (2013) A novel, highly sensitive method for assessing gap junctional coupling. J Neurosci Methods 220:18-23
Beaumont, Michael; Maccaferri, Gianmaria (2011) Is connexin36 critical for GABAergic hypersynchronization in the hippocampus? J Physiol 589:1663-80
Postma, Friso; Liu, Cheng-Hang; Dietsche, Caitlin et al. (2011) Electrical synapses formed by connexin36 regulate inhibition- and experience-dependent plasticity. Proc Natl Acad Sci U S A 108:13770-5
Brown, Timothy M; Allen, Annette E; Wynne, Jonathan et al. (2011) Visual responses in the lateral geniculate evoked by Cx36-independent rod pathways. Vision Res 51:280-7
Chai, Zhifang; Goodenough, Daniel A; Paul, David L (2011) Cx50 requires an intact PDZ-binding motif and ZO-1 for the formation of functional intercellular channels. Mol Biol Cell 22:4503-12
Magnotti, Laura M; Goodenough, Daniel A; Paul, David L (2011) Deletion of oligodendrocyte Cx32 and astrocyte Cx43 causes white matter vacuolation, astrocyte loss and early mortality. Glia 59:1064-74
Magnotti, Laura M; Goodenough, Daniel A; Paul, David L (2011) Functional heterotypic interactions between astrocyte and oligodendrocyte connexins. Glia 59:26-34
Pan, Feng; Paul, David L; Bloomfield, Stewart A et al. (2010) Connexin36 is required for gap junctional coupling of most ganglion cell subtypes in the mouse retina. J Comp Neurol 518:911-27
Imbeault, Sophie; Gauvin, Lianne G; Toeg, Hadi D et al. (2009) The extracellular matrix controls gap junction protein expression and function in postnatal hippocampal neural progenitor cells. BMC Neurosci 10:13
Hou, Jianghui; Renigunta, Aparna; Gomes, Antonio S et al. (2009) Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium. Proc Natl Acad Sci U S A 106:15350-5

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