Epistatic dissection of laminin - receptor interactions in dystrophic zebrafish muscle

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

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

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 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 localised and up-regulated in damaged fibres, which appears to contribute to fibre survival. Importantly, our results show that endogenous secretion of laminins from surrounding tissues has the potential to reinforce fibre attachments and strengthen laminin-ECM attachments. Together this will provide a better understanding of the cellular pathology of MDC1A and help in designing effective therapies.
Original languageEnglish
Pages (from-to)4718 - 4731
Number of pages14
JournalHuman Molecular Genetics
Volume21
Issue number21
DOIs
Publication statusPublished - 2012

Cite this

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title = "Epistatic dissection of laminin - receptor interactions in dystrophic zebrafish muscle",
abstract = "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 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 localised and up-regulated in damaged fibres, which appears to contribute to fibre survival. Importantly, our results show that endogenous secretion of laminins from surrounding tissues has the potential to reinforce fibre attachments and strengthen laminin-ECM attachments. Together this will provide a better understanding of the cellular pathology of MDC1A and help in designing effective therapies.",
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Epistatic dissection of laminin - receptor interactions in dystrophic zebrafish muscle. / Sztal, Tamar E; Sonntag, Carmen; Hall, Thomas E; Currie, Peter D.

In: Human Molecular Genetics, Vol. 21, No. 21, 2012, p. 4718 - 4731.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Sonntag, Carmen

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AB - 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 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 localised and up-regulated in damaged fibres, which appears to contribute to fibre survival. Importantly, our results show that endogenous secretion of laminins from surrounding tissues has the potential to reinforce fibre attachments and strengthen laminin-ECM attachments. Together this will provide a better understanding of the cellular pathology of MDC1A and help in designing effective therapies.

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