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Updated: May 10, 2026
Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
Published on: January 7, 2019
Genetic deletion of Cadm4 results in myelin abnormalities resembling Charcot-Marie-Tooth neuropathy
Neev Golan1, Elena Kartvelishvily, Ivo Spiegel
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
The interaction between myelinating Schwann cells and the axons they ensheath is mediated by cell adhesion molecules of the Cadm/Necl/SynCAM family. This family consists of four members: Cadm4/Necl4 and Cadm1/Necl2 are found in both glia and axons, whereas Cadm2/Necl3 and Cadm3/Necl1 are expressed by sensory and motor neurons. By generating mice lacking each of the Cadm genes, we now demonstrate that Cadm4 plays a role in the establishment of the myelin unit in the peripheral nervous system. Mice lacking Cadm4 (PGK-Cre/Cadm4(fl/fl)), but not Cadm1, Cadm2, or Cadm3, develop focal hypermyelination characterized by tomacula and myelin outfoldings, which are the hallmark of several Charcot-Marie-Tooth neuropathies. The absence of Cadm4 also resulted in abnormal axon-glial contact and redistribution of ion channels along the axon. These neuropathological features were also found in transgenic mice expressing a dominant-negative mutant of Cadm4 lacking its cytoplasmic domain in myelinating glia Tg(mbp-Cadm4dCT), as well as in mice lacking Cadm4 specifically in Schwann cells (DHH-Cre/Cadm4(fl/fl)). Consistent with these abnormalities, both PGK-Cre/Cadm4(fl/fl) and Tg(mbp-Cadm4dCT) mice exhibit impaired motor function and slower nerve conduction velocity. These findings indicate that Cadm4 regulates the growth of the myelin unit and the organization of the underlying axonal membrane.
Insights
Cadherin-M4 (Cadm4) is crucial for myelin sheath formation in the peripheral nervous system. Its absence causes myelin abnormalities and impaired motor function, highlighting its role in nerve health.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Cell adhesion molecules of the Cadm/Necl/SynCAM family mediate Schwann cell-axon interactions.
- This family has four members with distinct expression patterns in neurons and glia.
Purpose of the Study:
- To investigate the specific role of Cadm4 in peripheral nervous system myelination.
- To determine the function of Cadm4 in the establishment and maintenance of the myelin unit.
Main Methods:
- Generation and analysis of mice lacking individual Cadm genes (Cadm1-4).
- Utilized transgenic mice expressing a dominant-negative Cadm4 mutant.
- Specific knockout of Cadm4 in Schwann cells using DHH-Cre.
- Assessed neuropathological features, axon-glial contact, ion channel distribution, motor function, and nerve conduction velocity.
Main Results:
- Mice lacking Cadm4 exhibited focal hypermyelination, tomacula, and myelin outfoldings, characteristic of Charcot-Marie-Tooth neuropathies.
- Absence of Cadm4 led to abnormal axon-glial contact and ion channel redistribution.
- Transgenic mice with dominant-negative Cadm4 or Schwann cell-specific Cadm4 knockout showed similar neuropathological features.
- Cadm4-deficient mice displayed impaired motor function and reduced nerve conduction velocity.
Conclusions:
- Cadm4 is essential for the proper growth and organization of the myelin unit in the peripheral nervous system.
- Cadm4 regulates the interaction between myelinating Schwann cells and axons.
- Dysfunction of Cadm4 is linked to neuropathies and impaired nerve function.
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