title: Crim1 has cell-autonomous and paracrine roles during embryonic heart development.
abstract: The epicardium has a critical role during embryonic development, contributing epicardium-derived lineages to the heart, as well as providing regulatory and trophic signals necessary for myocardial development. Crim1 is a unique trans-membrane protein expressed by epicardial and epicardially-derived cells but its role in cardiogenesis is unknown. Using knockout mouse models, we observe that loss of Crim1 leads to congenital heart defects including epicardial defects and hypoplastic ventricular compact myocardium. Epicardium-restricted deletion of Crim1 results in increased epithelial-to-mesenchymal transition and invasion of the myocardium in vivo, and an increased migration of primary epicardial cells. Furthermore, Crim1 appears to be necessary for the proliferation of epicardium-derived cells (EPDCs) and for their subsequent differentiation into cardiac fibroblasts. It is also required for normal levels of cardiomyocyte proliferation and apoptosis, consistent with a role in regulating epicardium-derived trophic factors that act on the myocardium. Mechanistically, Crim1 may also modulate key developmentally expressed growth factors such as TGFβs, as changes in the downstream effectors phospho-SMAD2 and phospho-ERK1/2 are observed in the absence of Crim1. Collectively, our data demonstrates that Crim1 is essential for cell-autonomous and paracrine aspects of heart development.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Swati
authors.initials: S
authors.lastname: Iyer
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Fang Yu
authors.initials: FY
authors.lastname: Chou
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Han Sheng
authors.initials: HS
authors.lastname: Chiu
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Vinay K Sundar
authors.initials: VK
authors.lastname: Raju
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, Australia.|Murdoch Children's Research Institute, Melbourne, The University of Queensland, Brisbane, 4072, Australia.|Department of Pediatrics, University of Melbourne, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Little
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Walter G
authors.initials: WG
authors.lastname: Thomas
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Piper
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pennisi
mesh_terms: D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006321:Heart / Q000254:growth & development*; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics*; D019899:Paracrine Communication / Q000235:genetics; D010496:Pericardium / Q000196:embryology; D051899:Smad2 Protein / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: C518411:Crim1 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D053773:Transforming Growth Factor beta1; D052004:Bone Morphogenetic Protein Receptors
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