title: Grk5l controls heart development by limiting mTOR signaling during symmetry breaking.
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.
authors: Leibniz Institute for Age Research, Fritz Lippmann Institute, 07745 Jena, Germany.
authors: Martin D
authors: MD
authors: Burkhalter
authors: Gregory B
authors: GB
authors: Fralish
authors: Richard T
authors: RT
authors: Premont
authors: Marc G
authors: MG
authors: Caron
authors: Melanie
authors: M
authors: Philipp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006321:Heart / Q000196:embryology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D038081:Organogenesis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; D058570:TOR Serine-Threonine Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse; C586890:Grk5l protein, zebrafish
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