DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?

Journal of Cellular and Molecular Medicine

Alexandra Tassin³  Dalila Laoudj-Chenivesse¹  Céline Vanderplanck³  Marietta Barro¹  Sébastien Charron³  Eugénie Ansseau³  Yi-Wen Chen²  Jacques Mercier¹  Frédérique Coppée³ 

[1] INSERM U1046 Physiologie et Médecine expérimentale Cœur et Muscle, Montpellier, France;Children's National Medical Center, Center for Genetic Medicine Research, Washington, DC, USA;Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Belgium

关键词: FSHD;    DUX4;    homeodomain;    differentiation;    myoblasts;    PITX1;    muscle;    nucleus;   

DOI  :  10.1111/j.1582-4934.2012.01647.x

来源: Wiley

【 摘 要 】

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent hereditary muscle disorders. It is linked to contractions of the D4Z4 repeat array in 4q35. We have characterized the double homeobox 4 (DUX4) gene in D4Z4 and its mRNA transcribed from the distal D4Z4 unit to a polyadenylation signal in the flanking pLAM region. It encodes a transcription factor expressed in FSHD but not healthy muscle cells which initiates a gene deregulation cascade causing differentiation defects, muscle atrophy and oxidative stress. PITX1 was the first identified DUX4 target and encodes a transcription factor involved in muscle atrophy. DUX4 was found expressed in only 1/1000 FSHD myoblasts. We have now shown it was induced upon differentiation and detected in about 1/200 myotube nuclei. The DUX4 and PITX1 proteins presented staining gradients in consecutive myonuclei which suggested a diffusion as known for other muscle nuclear proteins. Both protein half-lifes were regulated by the ubiquitin-proteasome pathway. In addition, we could immunodetect the DUX4 protein in FSHD muscle extracts. As a model, we propose the DUX4 gene is stochastically activated in a small number of FSHD myonuclei. The resulting mRNAs are translated in the cytoplasm around an activated nucleus and the DUX4 proteins diffuse to adjacent nuclei where they activate target genes such as PITX1. The PITX1 protein can further diffuse to additional myonuclei and expand the transcriptional deregulation cascade initiated by DUX4. Together the diffusion and the deregulation cascade would explain how a rare protein could cause the muscle defects observed in FSHD.

【 授权许可】

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© 2012 The Authors Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

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