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Elife. 2016 Nov 14;5. pii: e11405. doi: 10.7554/eLife.11405.

Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy.

Author information

1
Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
2
Department of Cell and Developmental Biology, University College London, London, United Kingdom.
3
Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany.
4
Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany.
5
Centre of Human and Aerospace Physiological Sciences, King's College London, London, United Kingdom.
6
Craniofacial Development and Stem Cell Biology, King's College London, London, United Kingdom.

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 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.

KEYWORDS:

DUX4; FSHD; RET; Sunitinib; cell biology; facioscapulohumeral muscular dystrophy; human; human biology; medicine; mouse; therapy

PMID:
27841748
PMCID:
PMC5108591
DOI:
10.7554/eLife.11405
[Indexed for MEDLINE]
Free PMC Article

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