title: Cardiac malformations in Pdgfralpha mutant embryos are associated with increased expression of WT1 and Nkx2.5 in the second heart field.
abstract: Platelet-derived growth factor receptor alpha (Pdgfralpha) identifies cardiac progenitor cells in the posterior part of the second heart field. We aim to elucidate the role of Pdgfralpha in this region. Hearts of Pdgfralpha-deficient mouse embryos (E9.5-E14.5) showed cardiac malformations consisting of atrial and sinus venosus myocardium hypoplasia, including venous valves and sinoatrial node. In vivo staining for Nkx2.5 showed increased myocardial expression in Pdgfralpha mutants, confirmed by Western blot analysis. Due to hypoplasia of the primary atrial septum, mesenchymal cap, and dorsal mesenchymal protrusion, the atrioventricular septal complex failed to fuse. Impaired epicardial development and severe blebbing coincided with diminished migration of epicardium-derived cells and myocardial thinning, which could be linked to increased WT1 and altered alpha4-integrin expression. Our data provide novel insight for a possible role for Pdgfralpha in transduction pathways that lead to repression of Nkx2.5 and WT1 during development of posterior heart field-derived cardiac structures.
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Noortje A M
authors.initials: NA
authors.lastname: Bax
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bleyl
authors.forename: Radiosa
authors.initials: R
authors.lastname: Gallini
authors.forename: Lambertus J
authors.initials: LJ
authors.lastname: Wisse
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hunter
authors.forename: Angelique A M
authors.initials: AA
authors.lastname: Van Oorschot
authors.forename: Edris A F
authors.initials: EA
authors.lastname: Mahtab
authors.forename: Heleen
authors.initials: H
authors.lastname: Lie-Venema
authors.forename: Marie-Jose
authors.initials: MJ
authors.lastname: Goumans
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation; D006321:Heart / Q000254:growth & development; D006330:Heart Defects, Congenital / Q000235:genetics*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D039441:Integrin alpha4 / Q000235:genetics; D051379:Mice; D009154:Mutation; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D025721:WT1 Proteins; D039441:Integrin alpha4; D020796:Receptor, Platelet-Derived Growth Factor alpha