Journal Article

Epistatic dissection of laminin–receptor interactions in dystrophic zebrafish muscle

Tamar E. Sztal, Carmen Sonntag, Thomas E. Hall and Peter D. Currie

in Human Molecular Genetics

Volume 21, issue 21, pages 4718-4731
Published in print November 2012 | ISSN: 0964-6906
Published online July 2012 | e-ISSN: 1460-2083 | DOI:
Epistatic dissection of laminin–receptor interactions in dystrophic zebrafish muscle

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Laminins form essential components of the basement membrane and are integral to forming and maintaining muscle integrity. Mutations in the human Laminin-alpha2 (LAMA2) gene result in the most common form of congenital muscular dystrophy, MDC1A. We have previously identified a zebrafish model of MDC1A called candyfloss (caf), carrying a loss-of-function mutation in the zebrafish lama2 gene. In the skeletal muscle, laminins connect the muscle cell to the extracellular matrix (ECM) by binding either dystroglycan or integrins at the cell membrane. Through epistasis experiments, we have established that both adhesion systems individually contribute to the maintenance of fibre adhesions and exhibit muscle detachment phenotypes. However, larval zebrafish in which both adhesion systems are simultaneously genetically inactivated possess a catastrophic failure of muscle attachment that is far greater than a simple addition of individual phenotypes would predict. We provide evidence that this is due to other crucial laminins present in addition to Lama2, which aid muscle cell attachments and integrity. We have found that lama1 is important for maintaining attachments, whereas lama4 is localized and up-regulated in damaged fibres, which appears to contribute to fibre survival. Importantly, our results show that endogenous secretion of laminins from the surrounding tissues has the potential to reinforce fibre attachments and strengthen laminin–ECM attachments. Collectively these findings provide a better understanding of the cellular pathology of MDC1A and help in designing effective therapies.

Journal Article.  8041 words.  Illustrated.

Subjects: Genetics and Genomics

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