Braf -mutant Schwann cells divert to a repair phenotype to induce congenital demyelinating neuropathy
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.
Aldea Daniel、Mondielli Gr¨|goire、Bernard-Marissal Nathalie、Weiss Lauren A.、Etchevers Heather C.、Moreno Mathias、Quintana Patrice、Delague Val¨|rie、Marechal Elise、Barlier Anne
INSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityDepartment of Psychiatry and Behavioral Sciences, University of California||Institute for Human Genetics, University of CaliforniaINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille UniversityINSERM, MMG, U1251, MarMaRa Institute, Aix Marseille University||AP-HM, MMG, MarMaRa Institute, La Conception Hospital Laboratory of Molecular Biology
神经病学、精神病学基础医学分子生物学
rare diseasemosaicismsignalingneural crestdevelopment
Aldea Daniel,Mondielli Gr¨|goire,Bernard-Marissal Nathalie,Weiss Lauren A.,Etchevers Heather C.,Moreno Mathias,Quintana Patrice,Delague Val¨|rie,Marechal Elise,Barlier Anne.Braf -mutant Schwann cells divert to a repair phenotype to induce congenital demyelinating neuropathy[EB/OL].(2025-03-28)[2025-05-14].https://www.biorxiv.org/content/10.1101/2024.04.24.590951.点此复制
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