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Connexin32-null mice develop demyelinating peripheral neuropathy
S S Scherer1, Y T Xu, E Nelles
1Department of Neurology, University of Pennsylvania Medical Center, Philidelphia 19104-6077, USA. scherer@mail.med.upenn.edu
Abstract:
Mutations in the gene encoding the gap junction protein connexin32 (Cx32) cause X-linked Charcot-Marie-Tooth disease (CMTX), a common form of inherited demyelinating peripheral neuropathy. To learn more about the pathogenesis of CMTX, we examined the PNS and CNS of cx32-null mice (cx32-/Y males and cx32-/-females) by light and electron microscopy. These mice develop a progressive demyelinating peripheral neuropathy beginning by 3 months of age, and at all ages, motor fibers are more affected than sensory fibers. Like other genes of the X chromosome, the cx32 gene appears to be randomly inactivated, since only some myelinating Schwann cells express Cx32 in heterozygous cx32 +/- females. Heterozygous cx32 +/- females have fewer demyelinated and remyelinated axons than age-matched homozygous cx32-/- females and cx32-/Y males. Although oligodendrocytes also express Cx32, no abnormalities in CNS myelin were found. These findings indicate that a null cx32 allele in myelinating Schwann cells is sufficient to cause an inherited demyelinating neuropathy, so that Cx32 has an essential role in myelinating Schwann cells both in mice and in humans.
Insights
Mutations in connexin32 (Cx32) cause X-linked Charcot-Marie-Tooth disease (CMTX). Cx32-null mice show progressive demyelination, confirming Cx32
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mutations in connexin32 (Cx32) are a primary cause of X-linked Charcot-Marie-Tooth disease (CMTX), a prevalent inherited demyelinating peripheral neuropathy.
- Understanding the pathogenesis of CMTX is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of connexin32 (Cx32) in the pathogenesis of X-linked Charcot-Marie-Tooth disease (CMTX).
- To examine the effects of Cx32 deficiency on the peripheral nervous system (PNS) and central nervous system (CNS) in a mouse model.
Main Methods:
- Utilized light and electron microscopy to analyze the peripheral and central nervous systems of cx32-null mice (cx32-/Y males and cx32-/- females).
- Assessed the expression patterns of Cx32 in myelinating Schwann cells and oligodendrocytes.
Main Results:
- Cx32-null mice exhibit a progressive demyelinating peripheral neuropathy starting by 3 months of age, with motor fibers being more severely affected than sensory fibers.
- Heterozygous cx32+/- females displayed fewer demyelinated and remyelinated axons compared to homozygous cx32-/- females and cx32-/Y males.
- No abnormalities were observed in CNS myelin despite Cx32 expression in oligodendrocytes.
Conclusions:
- A null cx32 allele in myelinating Schwann cells is sufficient to induce inherited demyelinating neuropathy.
- Connexin32 plays an essential role in myelinating Schwann cells in both mice and humans, highlighting its significance in peripheral nerve health.