TY - JOUR TI - Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy AU - Moyle, Louise A AU - Blanc, Eric AU - Jaka, Oihane AU - Prueller, Johanna AU - Banerji, Christopher RS AU - Tedesco, Francesco Saverio AU - Harridge, Stephen DR AU - Knight, Robert D AU - Zammit, Peter S A2 - Rossant, Janet VL - 5 PY - 2016 DA - 2016/11/14 SP - e11405 C1 - eLife 2016;5:e11405 DO - 10.7554/eLife.11405 UR - https://doi.org/10.7554/eLife.11405 AB - Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, we over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD. RET is dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of either RET9 or RET51 increased myoblast proliferation, whereas siRNA-mediated knockdown of Ret induced myogenic differentiation. Suppressing RET activity using Sunitinib, a clinically-approved tyrosine kinase inhibitor, rescued differentiation in both DUX4-expressing murine myoblasts and in FSHD patient-derived myoblasts. Importantly, Sunitinib also increased engraftment and differentiation of FSHD myoblasts in regenerating mouse muscle. Thus, DUX4-mediated activation of Ret prevents myogenic differentiation and could contribute to FSHD pathology by preventing satellite cell-mediated repair. Rescue of DUX4-induced pathology by Sunitinib highlights the therapeutic potential of tyrosine kinase inhibitors for treatment of FSHD. KW - FSHD KW - RET KW - DUX4 KW - therapy KW - Sunitinib KW - facioscapulohumeral muscular dystrophy JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -