Abstract
The ClC-2 chloride channel is expressed in the plasma membrane of almost all mammalian cells. Mutations that cause the loss of ClC-2 function lead to retinal and testicular degeneration and leukodystrophy, whereas gain-of-function mutations cause hyperaldosteronism. Leukodystrophy is also observed with a loss of GlialCAM, a cell adhesion molecule that binds to ClC-2 in glia. GlialCAM changes the localization of ClC-2 and opens the channel by altering its gating. We now used cell type–specific deletion of ClC-2 in mice to show that retinal and testicular degeneration depend on a loss of ClC-2 in retinal pigment epithelial cells and Sertoli cells, respectively, whereas leukodystrophy was fully developed only when ClC-2 was disrupted in both astrocytes and oligodendrocytes. The leukodystrophy of Glialcam−/− mice could not be rescued by crosses with Clcn2op/op mice in which a mutation mimics the “opening” of ClC-2 by GlialCAM. These data indicate that GlialCAM-induced changes in biophysical properties of ClC-2 are irrelevant for GLIALCAM-related leukodystrophy. Taken together, our findings suggest that the pathology caused by Clcn2 disruption results from disturbed extracellular ion homeostasis and identifies the cells involved in this process.
Highlights
We argued that a cross with Clcn2op/op mice may rescue the leukodystrophy of Glialcam−/− mice if it is predominantly caused by a lack of ClC-2 opening
Cellular degeneration is not a cell-autonomous consequence of Clcn2 disruption but results from ClC-2 deletion in closely apposed neighboring cells on which the degenerating cells depend for their function and survival: loss of ClC-2 in Sertoli cells leads to the degeneration and eventual loss of male germ cells, whereas Clcn2 disruption in retinal pigment epithelial cells entails a rapid loss of photoreceptors
Using cell type–specific disruption of Clcn2 in mice, we identified those cell types in which ClC-2 must be present in order to prevent the degenerative pathologies observed upon the loss of the channel, i.e., azoospermia, photoreceptor degeneration, and spongiform myelin vacuolization
Summary
These include transepithelial transport, the modulation of cellular excitability, or the regulation of both intracellular and extracellular ion concentrations and of cell volume [1,2,3] Both loss- and gain-offunction mutations in diverse chloride channel genes, both in humans and animal models, result in a large spectrum of disease phenotypes. Regions and residues important for the slow opening of ClC-2 by hyperpolarization or cell swelling have been mapped to the amino terminus of ClC-2 [6] and an intracellular loop [10] Mutations in these regions virtually abolish gating and result in large Cl− currents with an almost ohmic behavior.
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