| First Author | Schiza N | Year | 2015 |
| Journal | Hum Mol Genet | Volume | 24 |
| Issue | 7 | Pages | 2049-64 |
| PubMed ID | 25524707 | Mgi Jnum | J:219594 |
| Mgi Id | MGI:5621234 | Doi | 10.1093/hmg/ddu725 |
| Citation | Schiza N, et al. (2015) Transgenic replacement of Cx32 in gap junction-deficient oligodendrocytes rescues the phenotype of a hypomyelinating leukodystrophy model. Hum Mol Genet 24(7):2049-64 |
| abstractText | Oligodendrocytes are coupled by gap junctions (GJs) formed mainly by connexin47 (Cx47) and Cx32. Recessive GJC2/Cx47 mutations cause Pelizaeus-Merzbacher-like disease, a hypomyelinating leukodystrophy, while GJB1/Cx32 mutations cause neuropathy and chronic or acute-transient encephalopathy syndromes. Cx32/Cx47 double knockout (Cx32/Cx47dKO) mice develop severe CNS demyelination beginning at 1 month of age leading to death within weeks, offering a relevant model to study disease mechanisms. In order to clarify whether the loss of oligodendrocyte connexins has cell autonomous effects, we generated transgenic mice expressing the wild-type human Cx32 under the control of the mouse proteolipid protein promoter, obtaining exogenous hCx32 expression in oligodendrocytes. By crossing these mice with Cx32KO mice, we obtained expression of hCx32 on Cx32KO background. Immunohistochemical and immunoblot analysis confirmed strong CNS expression of hCx32 specifically in oligodendrocytes and correct localization forming GJs at cell bodies and along the myelin sheath. TG(+)Cx32/Cx47dKO mice generated by further crossing with Cx47KO mice showed that transgenic expression of hCx32 rescued the severe early phenotype of CNS demyelination in Cx32/Cx47dKO mice, resulting in marked improvement of behavioral abnormalities at 1 month of age, and preventing the early mortality. Furthermore, TG(+)Cx32/Cx47dKO mice showed significant improvement of myelination compared with Cx32/Cx47dKO CNS at 1 month of age, while the inflammatory and astrogliotic changes were fully reversed. Our study confirms that loss of oligodendrocyte GJs has cell autonomous effects and that re-establishment of GJ connectivity by replacement of least one GJ protein provides correction of the leukodystrophy phenotype. |
