PUBLICATION

Grk5l Controls Heart Development by Limiting mTOR Signaling during Symmetry Breaking

Authors
Burkhalter, M.D., Fralish, G.B., Premont, R.T., Caron, M.G., and Philipp, M.
ID
ZDB-PUB-130904-35
Date
2013
Source
Cell Reports   4(4): 625-632 (Journal)
Registered Authors
Burkhalter, Martin, Philipp, Melanie
Keywords
none
MeSH Terms
  • Zebrafish
  • Signal Transduction
  • Amino Acid Sequence
  • Humans
  • Organogenesis
  • Mice
  • G-Protein-Coupled Receptor Kinase 5/chemistry
  • G-Protein-Coupled Receptor Kinase 5/genetics
  • G-Protein-Coupled Receptor Kinase 5/metabolism*
  • Body Patterning
  • Animals
  • HEK293 Cells
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Myocardium/metabolism*
  • Molecular Sequence Data
  • TOR Serine-Threonine Kinases/genetics
  • TOR Serine-Threonine Kinases/metabolism*
  • Heart/embryology*
(all 20)
PubMed
23972986 Full text @ Cell Rep.
Abstract

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.

Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
No data available
Human Disease / Model
No data available
Sequence Targeting Reagents
Target Reagent Reagent Type
grk3MO1-grk3MRPHLNO
grk5MO1-grk5MRPHLNO
grk5lMO1-grk5lMRPHLNO
grk5lMO2-grk5lMRPHLNO
grk5lMO3-grk5lMRPHLNO
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Fish
Antibodies
Orthology
Gene Orthology
grk5l
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Engineered Foreign Genes
No data available
Mapping
No data available