Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division
Nicolas A. Dumont,Nicolas A. Dumont,Yu Xin Wang,Yu Xin Wang,Julia von Maltzahn,Julia von Maltzahn,Alessandra Pasut,Alessandra Pasut,C. Florian Bentzinger,C. Florian Bentzinger,Caroline E. Brun,Caroline E. Brun,Michael A. Rudnicki,Michael A. Rudnicki +13 more
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TLDR
It is concluded that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division, and muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.Abstract:
Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.read more
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In vivo gene editing in dystrophic mouse muscle and muscle stem cells
Mohammadsharif Tabebordbar,Kexian Zhu,Jason Cheng,Wei Leong Chew,Jeffrey J. Widrick,Winston X. Yan,Winston X. Yan,Claire Maesner,Elizabeth Y Wu,Ru Xiao,F. Ann Ran,F. Ann Ran,Le Cong,Le Cong,Feng Zhang,Feng Zhang,Luk H. Vandenberghe,George M. Church,Amy J. Wagers +18 more
TL;DR: In this paper, the authors developed and tested a direct gene-editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of Duchenne muscular dystrophy.
In vivo gene editing in dystrophic mouse muscle and muscle stem cells
Mohammadsharif Tabebordbar,Kexian Zhu,Jason Cheng,Wei Leong Chew,Jeffrey J. Widrick,Claire Maesner,Elizabeth Y Wu,Ru Xiao,Fei Ran,Luk H. Vandenberghe,George M. Church,Amy J. Wagers,Winston X. Yan,Le Cong,Feng Zhang +14 more
TL;DR: A direct gene-editing approach is developed and tested to induce exon deletion and recover dystrophin expression in the mdx mouse model of DMD and partially recovered muscle functional deficiencies and generated a pool of endogenously corrected myogenic precursors in m dx mouse muscle.
Journal ArticleDOI
Detection of unamplified target genes via CRISPR–Cas9 immobilized on a graphene field-effect transistor
Reza Hajian,Sarah Balderston,Thanhtra P. Tran,Tara R. deBoer,Jessy Etienne,Mandeep Sandhu,Noreen A. Wauford,Jing-Yi Chung,Jolie Nokes,Mitre Athaiya,Jacobo Paredes,Regis Peytavi,Brett R. Goldsmith,Niren Murthy,Irina M. Conboy,Kiana Aran,Kiana Aran +16 more
TL;DR: An electrical biosensor combining CRISPR–Cas9 and a graphene field-effect transistor detects target genes in purified genomic samples at high sensitivity, within 15 minutes, and without the need for amplification.
Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA
F. Gleason,R. Chollet +1 more
Journal ArticleDOI
Duchenne muscular dystrophy.
TL;DR: In this article, the authors present guidelines for the multidisciplinary care for Duchenne muscular dystrophy that address obtaining a genetic diagnosis and managing the various aspects of the disease.
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