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Cellular basis of ClC-2 Cl- channel-related brain and testis pathologies
Corinna Göppner1, Audrey H Soria1, Maja B Hoegg-Beiler1
1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
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.
Insights
Loss of ClC-2 chloride channels in specific cells causes retinal, testicular, and brain diseases. GlialCAM
Area of Science:
- Cellular Biology
- Neuroscience
- Genetics
Background:
- The ClC-2 chloride channel is vital, with mutations causing retinal and testicular degeneration and leukodystrophy.
- GlialCAM, a cell adhesion molecule, interacts with ClC-2 in glia, affecting its localization and gating.
Purpose of the Study:
- To determine the cell types responsible for ClC-2-related pathologies using cell type-specific gene deletion in mice.
- To investigate the role of GlialCAM-ClC-2 interaction in GlialCAM-deficient leukodystrophy.
Main Methods:
- Cell type-specific deletion of the Clcn2 gene in mice.
- Genetic crosses between Glialcam knockout mice and Clcn2 mutant mice.
Main Results:
- Retinal and testicular degeneration result from ClC-2 loss in retinal pigment epithelial and Sertoli cells, respectively.
- Leukodystrophy requires ClC-2 disruption in both astrocytes and oligodendrocytes.
- GlialCAM-deficiency-induced leukodystrophy is not rescued by a ClC-2 gain-of-function mutation, suggesting GlialCAM's effect is independent of ClC-2 gating.
Conclusions:
- ClC-2's role in disease is cell-type specific.
- GlialCAM-related leukodystrophy does not depend on altered ClC-2 biophysical properties.
- Pathologies from Clcn2 disruption stem from disrupted extracellular ion homeostasis, with specific glial cells being key players.
