title: Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy.
abstract: 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 kinaseRetwas significantly up-regulated, suggesting a role in FSHD.RETis dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of eitherRET9orRET51increased myoblast proliferation, whereas siRNA-mediated knockdown ofRetinduced 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 ofRetprevents 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.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.|Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Moyle
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.|Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany.|Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Blanc
authors.affiliation: Centre of Human and Aerospace Physiological Sciences, King's College London, London, United Kingdom.
authors.forename: Oihane
authors.initials: O
authors.lastname: Jaka
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Johanna
authors.initials: J
authors.lastname: Prueller
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Christopher Rs
authors.initials: CR
authors.lastname: Banerji
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Francesco Saverio
authors.identifier: 0000-0001-5321-7682
authors.initials: FS
authors.lastname: Tedesco
authors.affiliation: Centre of Human and Aerospace Physiological Sciences, King's College London, London, United Kingdom.
authors.forename: Stephen Dr
authors.initials: SD
authors.lastname: Harridge
authors.affiliation: Craniofacial Development and Stem Cell Biology, King's College London, London, United Kingdom.
authors.forename: Robert D
authors.identifier: 0000-0001-9920-836X
authors.initials: RD
authors.lastname: Knight
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Peter S
authors.identifier: 0000-0001-9562-3072
authors.initials: PS
authors.lastname: Zammit
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D009132:Muscles / Q000166:cytology*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000188:drug therapy*; D032446:Myoblasts / Q000187:drug effects / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000627:therapeutic use*; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000502:physiology*; D000077210:Sunitinib
chemical_list: C121257:DUX4L1 protein, human; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D007211:Indoles; D011758:Pyrroles; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D000077210:Sunitinib
keywords: DUX4; FSHD; RET; Sunitinib; cell biology; facioscapulohumeral muscular dystrophy; human; human biology; medicine; mouse; therapy