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.