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Lamin Mutations Cause Increased YAP Nuclear Entry in Muscle Stem Cells

Owens, DJ, Fischer, M, Jabre, S, Moog, S, Mamchoui, K, Butler-Browne, G and Coirault, C (2020) Lamin Mutations Cause Increased YAP Nuclear Entry in Muscle Stem Cells. Cells, 9 (4). ISSN 2073-4409

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Mutations in the LMNA gene, encoding the nuclear envelope A-type lamins, are responsible for muscular dystrophies, the most severe form being the LMNA-related congenital muscular dystrophy (L-CMD), with severe defects in myonucleus integrity. We previously reported that L-CMD mutations compromise the ability of muscle stem cells to modulate the yes-associated protein (YAP), a pivotal factor in mechanotransduction and myogenesis. Here, we investigated the intrinsic mechanisms by which lamins influence YAP subcellular distribution, by analyzing different conditions affecting the balance between nuclear import and export of YAP. In contrast to wild type (WT) cells, LMNADK32 mutations failed to exclude YAP from the nucleus and to inactivate its transcriptional activity at high cell density, despite activation of the Hippo pathway. Inhibiting nuclear pore import abolished YAP nuclear accumulation in confluent mutant cells, thus showing persistent nuclear import of YAP at cell confluence. YAP deregulation was also present in congenital myopathy related to nesprin-1KASH mutation, but not in cells expressing the LMNAH222P mutation, the adult form of lamin-related muscle dystrophy with reduced nuclear deformability. In conclusion, our data showed that L-CMD mutations increased YAP nuclear localization via an increased nuclear import and implicated YAP as a pathogenic contributor in muscle dystrophies caused by nuclear envelop defects.

Item Type: Article
Subjects: R Medicine > RC Internal medicine > RC1200 Sports Medicine
Divisions: Sport & Exercise Sciences
Publisher: MDPI AG
Date Deposited: 01 Apr 2020 08:43
Last Modified: 04 Sep 2021 07:33
DOI or ID number: 10.3390/cells9040816
URI: https://researchonline.ljmu.ac.uk/id/eprint/12622
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