Loss of zebrafish Smyd1a interferes with myofibrillar integrity without triggering the misfolded myosin response

Paone, C., Rudeck, S., Etard, C., Strähle, U., Rottbauer, W., Just, S.
Biochemical and Biophysical Research Communications   496(2): 339-345 (Journal)
Registered Authors
Etard, Christelle, Just, Steffen, Rottbauer, Wolfgang, Rudeck, Steven, Strähle, Uwe
CRISPR/Cas9, Cardiomyocyte, Danio rerio, Misfolded myosin response, Skeletal muscle, Smyd1, mBop
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • CRISPR-Cas Systems
  • Embryo, Nonmammalian
  • Gene Duplication
  • Gene Editing
  • Gene Expression Regulation, Developmental*
  • Genes, Reporter
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • HSP90 Heat-Shock Proteins/genetics
  • HSP90 Heat-Shock Proteins/metabolism
  • Histone-Lysine N-Methyltransferase/antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase/deficiency
  • Histone-Lysine N-Methyltransferase/genetics*
  • Humans
  • Molecular Chaperones/genetics
  • Molecular Chaperones/metabolism
  • Morpholinos/genetics
  • Morpholinos/metabolism
  • Muscle, Skeletal/metabolism*
  • Muscle, Skeletal/pathology
  • Myocytes, Cardiac/metabolism*
  • Myocytes, Cardiac/pathology
  • Myosins/genetics*
  • Myosins/metabolism
  • Protein Folding
  • Protein Isoforms/deficiency
  • Protein Isoforms/genetics
  • Sarcomeres/metabolism*
  • Sarcomeres/pathology
  • Zebrafish/genetics*
  • Zebrafish/growth & development
  • Zebrafish/metabolism
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
29331378 Full text @ Biochem. Biophys. Res. Commun.
Sarcomeric protein turnover needs to be tightly balanced to assure proper assembly and renewal of sarcomeric units within muscle tissues. The mechanisms regulating these fundamental processes are only poorly understood, but of great clinical importance since many cardiac and skeletal muscle diseases are associated with defective sarcomeric organization. The SET- and MYND domain containing protein 1b (Smyd1b) is known to play a crucial role in myofibrillogenesis by functionally interacting with the myosin chaperones Unc45b and Hsp90α1. In zebrafish, Smyd1b, Unc45b and Hsp90α1 are part of the misfolded myosin response (MMR), a regulatory transcriptional response that is activated by disturbed myosin homeostasis. Genome duplication in zebrafish led to a second smyd1 gene, termed smyd1a. Morpholino- and CRISPR/Cas9-mediated knockdown of smyd1a led to significant perturbations in sarcomere structure resulting in decreased cardiac as well as skeletal muscle function. Similar to Smyd1b, we found Smyd1a to localize to the sarcomeric M-band in skeletal and cardiac muscles. Overexpression of smyd1a efficiently compensated for the loss of Smyd1b in flatline (fla) mutant zebrafish embryos, rescued the myopathic phenotype and suppressed the MMR in Smyd1b-deficient embryos, suggesting overlapping functions of both Smyd1 paralogs. Interestingly, Smyd1a is not transcriptionally activated in Smyd1b-deficient fla mutants, demonstrating lack of genetic compensation despite the functional redundancy of both zebrafish Smyd1 paralogs.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes