title: Scrib:Rac1 interactions are required for the morphogenesis of the ventricular myocardium.
abstract: OBJECTIVE
  The organization and maturation of ventricular cardiomyocytes from the embryonic to the adult form is crucial for normal cardiac function. We have shown that a polarity protein, Scrib, may be involved in regulating the early stages of this process. Our goal was to establish whether Scrib plays a cell autonomous role in the ventricular myocardium, and whether this involves well-known polarity pathways.
  
  
  RESULTS
  Deletion of Scrib in cardiac precursors utilizing Scrib(flox) mice together with the Nkx2.5-Cre driver resulted in disruption of the cytoarchitecture of the forming trabeculae and ventricular septal defects. Although the majority of mice lacking Scrib in the myocardium survived to adulthood, they developed marked cardiac fibrosis. Scrib did not physically interact with the planar cell polarity (PCP) protein, Vangl2, in early cardiomyocytes as it does in other tissues, suggesting that the anomalies did not result from disruption of PCP signalling. However, Scrib interacted with Rac1 physically in embryonic cardiomyocytes and genetically to result in ventricular abnormalities, suggesting that this interaction is crucial for the development of the early myocardium.
  
  
  CONCLUSIONS
  The Scrib-Rac1 interaction plays a crucial role in the organization of developing cardiomyocytes and formation of the ventricular myocardium. Thus, we have identified a novel signalling pathway in the early, functioning, heart muscle. These data also show that the foetus can recover from relatively severe abnormalities in prenatal ventricular development, although cardiac fibrosis can be a long-term consequence.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Veronika
authors.initials: V
authors.lastname: Boczonadi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gillespie
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Keenan
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Ramsbottom
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Donald-Wilson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Mariana
authors.initials: M
authors.lastname: Al Nazer
authors.affiliation: Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Melbourne, Australia Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Melbourne, Australia Department of Pathology, University of Melbourne, Parkville, Melbourne, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Humbert
authors.affiliation: University of Houston, Houston, TX, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwarz
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Bill
authors.initials: B
authors.lastname: Chaudhry
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK deborah.henderson@ncl.ac.uk.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Henderson
mesh_terms: D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D053595:Embryonic Stem Cells / Q000378:metabolism; D005355:Fibrosis; D005838:Genotype; D005865:Gestational Age; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D046912:Multiprotein Complexes; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; D020830:rac1 GTP-Binding Protein; C576607:Arhgef7 protein, mouse; C431577:Ltap protein, mouse; C484602:Rac1 protein, mouse; C508433:scrib protein, mouse; C548802:scribble protein, rat; C499134:Rac1 protein, rat
keywords: Cardiac development; Cardiomyocytes; Polarity; Rac1; Scrib; Ventricular myocardium