Braf-mutant Schwann cells divert to a repair phenotype to induce congenital demyelinating neuropathy

Abstract

RASopathies are developmental disorders associated with mutations leading to constitutive activation of the Mitogen Activated Protein Kinase (MAPK) signaling pathway. Peripheral nerve enlargement and damage are recently reported symptoms in germline RASopathy patients. We characterized mouse models in which a frequent mutation of the MAPK effector Braf (V600E) in mosaic RASopathies is expressed in embryonic progenitors of Schwann cells. Postnatal mice develop an early, fully penetrant degenerative peripheral neuropathy. Symptoms appear before weaning, with sciatic nerve enlargement, loss of hindlimb muscle strength, and failure to thrive relative to littermates. The V600E catalytic domain mutation promotes expansion of a Jun+ Schwann cell repair state at the expense of mature, myelinating Schwann cells, preventing full peripheral myelination. Associated with the germline RASopathy cardio-facio-cutaneous syndrome, the BRAF (Q257R) mutation also prevents terminal differentiation of Schwann cells from patient-derived induced pluripotent stem cells. This study supports the likelihood that some of the genetic heterogeneity in human peripheral neuropathies may be imputed to somatic mosaicism in a contextually underexplored pathway. It also provides a mechanistic explanation for RASopathy-associated neuropathies.