How does connexin expression affect oligodendrocyte function?

Nadine Richter, Christiane Nolte

 

The Importance of Glial Cell-to-Cell Communication via Gap Junction Proteins (Connexins)

The glial cell-to-cell communication via gap junctions is vital for glial cells to maintain proper brain function. This is underlined by genetic evidence showing that mutations in gap junction proteins (connexins) can cause a variety of human brain diseases such as leukodystrophies.

In collaboration with Prof. Willecke’s group in Bonn we developed and characterized a mouse model of Pelizaeus-Merzbacher-like-disease (PMLD1). PMLD is a childhood leukodystrophy caused by mutations in the human Connexin47 gene. The pathologic and phenotypic alterations in this model suggest that PMLD1 is caused by the loss of the oligodendrocytic Cx47 channel function and results in impaired coupling in white matter tissue (Tress et al., 2011).

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Confocal image of the biocytin/ streptavidin-Cy3 (red) labelled network immunostained for the oligodendrocyte marker CNPase (green) and astrocyte marker GFAP (blue). A single oligodendrocyte was injected with the gap junction permeable tracer biocytin by whole-cell patch clamp. The majority of coupled cells were identified as CNPase expressing oligodendrocytes.

 

 

Our most recent study revealed a complete disruption of oligodendrocyte to astrocyte coupling in the white matter of 10-15day old Cx30/Cx47 double deficient mice. Histological and ultrastructural analyses revealed severe vacuolization and myelination defects in all white matter tracts of the CNS. These findings give us the possibility to better understand the functional differences of glial connexins and their important role in the CNS (Tress et al., 2012).

 

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White matter pathology in cerebellum and corpus callosum of P80-P90 Cx30-/-/Cx47-/- mice. A,B) Images show severe vacuolization of cerebellar white matter in Cx30-/-/Cx47-/- mice compared to Cx30+/-/Cx47+/- controls. C, D) Ultrathin sections of cerebellar white matter revealed vacuoles located at the outer layer of myelin in Cx30-/-/Cx47-/-  mice (asterisks) which were not observed in Cx30+/-/Cx47+/-  animals (Tress et al., 2012)

 

 

 

 

 

Tress O, Maglione M, May D, Pivneva T, Richter N, Seyfarth J, Binder S, Zlomuzica A, Seifert G, Theis M, Dere E, Kettenmann H, Willecke K. Panglial gap junctional communication is essential for maintenance of myelin in the CNS. J Neurosci. 2012 May 30;32(22):7499-518.