PUBLICATION

Epistatic dissection of laminin-receptor interactions in dystrophic zebrafish muscle

Authors
Sztal, T.E., Sonntag, C., Hall, T.E., and Currie, P.D.
ID
ZDB-PUB-120807-39
Date
2012
Source
Human molecular genetics   21(21): 4718-4731 (Journal)
Registered Authors
Currie, Peter D., Hall, Thomas, Sonntag, Carmen, Sztal, Tamar Esther
Keywords
none
MeSH Terms
  • Animals
  • Dystroglycans/metabolism
  • Epistasis, Genetic*
  • Extracellular Matrix/metabolism
  • Humans
  • Laminin*/genetics
  • Laminin*/metabolism
  • Muscle Development/genetics*
  • Muscle, Skeletal*/cytology
  • Muscle, Skeletal*/growth & development
  • Muscle, Skeletal*/metabolism
  • Muscular Dystrophies/genetics
  • Muscular Dystrophies/metabolism
  • Muscular Dystrophies/physiopathology
  • Muscular Dystrophy, Animal/genetics
  • Muscular Dystrophy, Animal/metabolism
  • Muscular Dystrophy, Animal/pathology
  • Protein Binding
  • Receptors, Laminin/genetics
  • Zebrafish
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
PubMed
22859503 Full text @ Hum. Mol. Genet.
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.

Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping