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ZFIN ID: ZDB-PUB-130904-35
Grk5l Controls Heart Development by Limiting mTOR Signaling during Symmetry Breaking
Burkhalter, M.D., Fralish, G.B., Premont, R.T., Caron, M.G., and Philipp, M.
Date: 2013
Source: Cell Reports   4(4): 625-632 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Body Patterning
  • G-Protein-Coupled Receptor Kinase 5/chemistry
  • G-Protein-Coupled Receptor Kinase 5/genetics
  • G-Protein-Coupled Receptor Kinase 5/metabolism*
  • HEK293 Cells
  • Heart/embryology*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Myocardium/metabolism*
  • Organogenesis
  • Signal Transduction
  • TOR Serine-Threonine Kinases/genetics
  • TOR Serine-Threonine Kinases/metabolism*
  • Zebrafish
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 23972986 Full text @ Cell Rep.

The correct asymmetric placement of inner organs is termed situs solitus and is determined early during development. Failure in symmetry breaking results in conditions ranging from randomized organ arrangement to a complete mirror image, often accompanied by severe congenital heart defects (CHDs). We found that the zebrafish homolog of mammalian G protein-coupled receptor kinase 5 (GRK5) employs noncanonical, receptor-independent functions to secure symmetry breaking. Knockdown of GRK5's closest homolog in zebrafish embryos, Grk5l, is sufficient to randomize cardiac looping and left-right asymmetry. Mechanistically, we found that loss of GRK5 increases mammalian target of rapamycin complex 1 (mTORC1) activity. This causes elongation of motile cilia in the organ of laterality, a consequence that is known to be sufficient to trigger aberrant organ arrangement. By fine-tuning mTORC1, GRK5 thus serves an unanticipated function during early development, besides its well-characterized role in the adult heart. These findings could implicate GRK5 as a susceptibility allele for certain cases of CHD.