title: Fgf8 is required for anterior heart field development.
abstract: In the mouse embryo, the splanchnic mesodermal cells of the anterior heart field (AHF) migrate from the pharynx to contribute to the early myocardium of the outflow tract (OT) and right ventricle (RV). Recent studies have attempted to distinguish the AHF from other precardiac populations, and to determine the genetic and molecular mechanisms that regulate its development. Here, we have used an Fgf8lacZ allele to demonstrate that Fgf8 is expressed within the developing AHF. In addition, we use both a hypomorphic Fgf8 allele (Fgf8neo) and Cre-mediated gene ablation to show that Fgf8 is essential for the survival and proliferation of the AHF. Nkx2.5Cre is expressed in the AHF, primary heart tube and pharyngeal endoderm, while TnT-Cre is expressed only within the specified heart tube myocardium. Deletion of Fgf8 by Nkx2.5Cre results in a significant loss of the Nkx2.5Cre lineage and severe OT and RV truncations by E9.5, while the remaining heart chambers (left ventricle and atria) are grossly normal. These defects result from significant decreases in cell proliferation and aberrant cell death in both the pharyngeal endoderm and splanchnic mesoderm. By contrast, ablation of Fgf8 in the TnT-Cre domain does not result in OT or RV defects, providing strong evidence that Fgf8 expression is crucial in the pharyngeal endoderm and/or overlying splanchnic mesoderm of the AHF at a stage prior to heart tube elongation. Analysis of downstream signaling components, such as phosphorylated-Erk and Pea3, identifies the AHF splanchnic mesoderm itself as a target for Fgf8 signaling.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Ilagan
authors.forename: Radwan
authors.initials: R
authors.lastname: Abu-Issa
authors.forename: Doris
authors.initials: D
authors.lastname: Brown
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Kai
authors.initials: K
authors.lastname: Jiao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: John
authors.initials: J
authors.lastname: Klingensmith
authors.forename: Erik N
authors.initials: EN
authors.lastname: Meyers
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D001934:Branchial Region / Q000033:anatomy & histology / Q000378:metabolism; D018376:Cardiovascular Abnormalities; D019465:Craniofacial Abnormalities; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006321:Heart / Q000033:anatomy & histology* / Q000196:embryology* / Q000254:growth & development; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C496457:Fgf8 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; C065788:transcription factor PEA3; D051524:Fibroblast Growth Factor 8; D048049:Extracellular Signal-Regulated MAP Kinases