Résumé :
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Neurofibromatosis type I (NF1) is an inheritable disease caused by mutations in the NF1 gene encoding a Ras-GAP protein that negatively regulates Ras signalling.Besides neuroectodermal malformations and tumours, the skeletal system is often affected, with scoliosis, kyphosis and long bone dysplasias being a main cause ofmorbidity decreasing the patients quality of life. Reduction of muscle strength and size has also been reported in individual patients, suggesting a complex musculoskeletalpathogenesis in NF1. However, it is so far unclear whether a primary defect within muscles exists in NF1 or if the reduction in muscle strength might be secondary toskeletal malformations and tumour burden. We therefore analyzed skeletal muscle development in a mouse model for NF1, where the Nf1 gene was conditionallyinactivated in limb bud mesenchyme using the Prx1-Cre driver line (Nf1Prx1). Adult Nf1Prx1 mice displayed a pronounced dystrophic phenotype characterised by musclefibrosis, reduced number of muscle fibres, and reduced muscle force. This was preceded by an early defect in myogenesis in mid-gestation affecting the terminaldifferentiation of myoblasts between embryonic days (E) 12.5 and E14.5. In parallel the muscle connective tissue cells exhibited increased proliferation at E14.5 andtheir number increased as early as E16.5. These changes were accompanied by excessive MAPK pathway activation. This suggests that Nf1 is required for normalembryonic muscle formation and for limiting connective tissue proliferation thus counteracting fibrosis. Importantly, hip joint fusion and kyphosis, two prominent skeletalphenotypes in Nf1Prx1 mice, are preceded by and coincide with defects in muscle development, suggesting that aspects of the skeletal pathology in Nf1Prx1 mice andprobably in NF1 patients are caused by previously unrecognized defects of skeletal muscle development and homeostasis.
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