Abstract
The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC)–axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc)155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease.
Highlights
Myelinated axons are organized in distinct molecular domains, the axon initial segment, the internodes, juxtaparanodes, paranodes, and the node of Ranvier
Consistent with previous studies using the same P0CreERT2 mouse line [22], recombination efficiency was variable between animals: histone deacetylases 1 and 2 (HDAC1/2) were ablated in 45% to 85% of Schwann cell (SC)
These data demonstrate that HDAC1/2 are essential in SCs to maintain adult peripheral nervous system (PNS) function
Summary
Myelinated axons are organized in distinct molecular domains, the axon initial segment, the internodes, juxtaparanodes, paranodes, and the node of Ranvier. In the peripheral nervous system (PNS), formation of these specialized domains requires the tight association of axons with Schwann cells (SCs), the myelinating glia of the PNS, except for the axon initial segment that forms independently of glial cells. Disruption of these domains causes or aggravates many human disorders of the nervous system, including multiple sclerosis, motor and sensory neuropathies, Guillain-Barré syndrome, and most likely cognitive disorders [1,2,3,4,5,6]. Our knowledge is incomplete and more work is required to fully understand the mechanisms that control their formation and preservation
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