{"doi":"10.1101/2024.04.24.590951","title":"Oncogenic MAPK pathway activation disrupts Schwann cell fate commitment, inducing congenital and progressive neuropathy in mice","abstract":"Abstract RASopathies, rare congenital syndromes affecting multiple organ systems, often include peripheral neuropathy of unknown origin. While RASopathy-associated gene variants are proto-oncogenic, the impact of timing and mosaicism on pathogenicity remains poorly understood. Here, we investigate the links between Braf, a key mitogen-activated protein kinase (MAPK) effector, and peripheral neuropathy. By targeting Braf p.V600E, an oncogenic variant found in mosaic RASopathies, to embryonic Mpz-expressing cells in mice, we induced a congenital Charcot-Marie-Tooth-like degenerative neuropathy. This phenotype was characterized by hyperplastic nerves, hindlimb weakness, and unexpectedly reduced body size. Constitutively active Braf expanded a Jun+ Schwann cell repair state, impairing myelination and nerve homeostasis. To examine relevance to RASopathies, we differentiated patient-derived stem cells bearing the cardio-facio-cutaneous syndrome-associated BRAF p.Q257R variant into Schwann cells. Compared to wild-type controls, CFC-derived cells failed to acquire mature phenotypes, instead exhibiting progenitor or repair-type transcriptional profiles. Our findings implicate somatic mosaicism in the unresolved genetic heterogeneity of neuropathies and expand the candidate gene list for peripheral nerve disorders. Moreover, they reveal a MAPK-dependent mechanism linking neural crest-derived Schwann cell dysfunction to both body growth and nerve homeostasis, providing new insights into the mechanisms in RASopathy-associated neuropathy and potential therapeutic targets.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":490784,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9633,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":656754,"name":"Daniel Aldea","orcid":"0000-0001-5101-0194","position":1,"is_corresponding":false},{"id":1335985,"name":"Patrice Quintana","orcid":"0000-0002-2198-2248","position":2,"is_corresponding":false},{"id":1171559,"name":"Grégoire Mondielli","orcid":"0000-0001-9608-7961","position":3,"is_corresponding":false},{"id":1335986,"name":"Nathalie Bernard-Marissal","orcid":"0000-0003-4272-9150","position":4,"is_corresponding":false},{"id":1335987,"name":"Mathias Moreno","orcid":"0000-0002-7057-0063","position":5,"is_corresponding":false},{"id":1335988,"name":"Claire El Yazidi","orcid":"0000-0002-0075-6719","position":6,"is_corresponding":false},{"id":1335989,"name":"Natacha Broucqsault","orcid":"0000-0001-8503-2981","position":7,"is_corresponding":false},{"id":1110119,"name":"Valérie Delague","orcid":"0000-0003-2652-362X","position":8,"is_corresponding":false},{"id":556291,"name":"Lauren A. Weiss","orcid":"0000-0002-5700-135X","position":9,"is_corresponding":false},{"id":399747,"name":"Anne Barlier","orcid":"0000-0002-3740-6173","position":10,"is_corresponding":false},{"id":71648,"name":"Heather C. Etchevers","orcid":"0000-0003-0201-3799","position":11,"is_corresponding":false},{"id":1335984,"name":"Elise Maréchal","orcid":"0000-0003-4586-3304","position":0,"is_corresponding":true}],"reference_count":129,"raw_metadata":null,"created_at":"2026-07-19T02:08:37.162700Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}