title: AcvR1-mediated BMP signaling in second heart field is required for arterial pole development: implications for myocardial differentiation and regional identity.
abstract: BMP signaling plays an essential role in second heart field-derived heart and arterial trunk development, including myocardial differentiation, right ventricular growth, and interventricular, outflow tract and aortico-pulmonary septation. It is mediated by a number of different BMP ligands, and receptors, many of which are present simultaneously. The mechanisms by which they regulate morphogenetic events and degree of redundancy amongst them have still to be elucidated. We therefore assessed the role of BMP Type I receptor AcvR1 in anterior second heart field-derived cell development, and compared it with that of BmpR1a. By removing Acvr1 using the driver Mef2c[AHF]-Cre, we show that AcvR1 plays an essential role in arterial pole morphogenesis, identifying defects in outflow tract wall and cushion morphology that preceded a spectrum of septation defects from double outlet right ventricle to common arterial trunk in mutants. Its absence caused dysregulation in gene expression important for myocardial differentiation (Isl1, Fgf8) and regional identity (Tbx2, Tbx3, Tbx20, Tgfb2). Although these defects resemble to some degree those in the equivalent Bmpr1a mutant, a novel gene knock-in model in which Bmpr1a was expressed in the Acvr1 locus only partially restored septation in Acvr1 mutants. These data show that both BmpR1a and AcvR1 are needed for normal heart development, in which they play some non-redundant roles, and refine our understanding of the genetic and morphogenetic processes underlying Bmp-mediated heart development important in human congenital heart disease.
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan - Ann Arbor, 1011 N. University Ave, Ann Arbor, MI 48109, USA.
authors.forename: Penny S
authors.initials: PS
authors.lastname: Thomas
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan - Ann Arbor, 1011 N. University Ave, Ann Arbor, MI 48109, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Rajderkar
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan - Ann Arbor, 1011 N. University Ave, Ann Arbor, MI 48109, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Lane
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan - Ann Arbor, 1011 N. University Ave, Ann Arbor, MI 48109, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan - Ann Arbor, 1011 N. University Ave, Ann Arbor, MI 48109, USA. Electronic address: vesak@umich.edu.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001158:Arteries / Q000196:embryology*; D019521:Body Patterning / Q000502:physiology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055879:Gene Knock-In Techniques; D005822:Genetic Vectors / Q000235:genetics; D006321:Heart / Q000196:embryology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: BMP signaling; Cardiac development; Conotruncal defects; Receptors; Second heart field