Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling.
Fibroblast growth factor 8 (Fgf8) is a secreted signaling protein expressed in numerous temporospatial domains that are potentially relevant to cardiovascular development. However, the pathogenesis of complex cardiac and outflow tract defects observed in Fgf8-deficient mice, and the specific source(s) of Fgf8 required for outflow tract formation and subsequent remodeling are unknown. A detailed examination of the timing and location of Fgf8 production revealed previously unappreciated expression in a subset of primary heart field cells; Fgf8 is also expressed throughout the anterior heart field (AHF) mesoderm and in pharyngeal endoderm at the crescent and early somite stages. We used conditional mutagenesis to examine the requirements for Fgf8 function in these different expression domains during heart and outflow tract morphogenesis. Formation of the primary heart tube and the addition of right ventricular and outflow tract myocardium depend on autocrine Fgf8 signaling in cardiac crescent mesoderm. Loss of Fgf8 in this domain resulted in decreased expression of the Fgf8 target gene Erm, and aberrant production of Isl1 and its target Mef2c in the anterior heart field, thus linking Fgf8 signaling with transcription factor networks that regulate survival and proliferation of the anterior heart field. We further found that mesodermal- and endodermal-derived Fgf8 perform specific functions during outflow tract remodeling: mesodermal Fgf8 is required for correct alignment of the outflow tract and ventricles, whereas activity of Fgf8 emanating from pharyngeal endoderm regulates outflow tract septation. These findings provide a novel insight into how the formation and remodeling of primary and anterior heart field-derived structures rely on Fgf8 signals from discrete temporospatial domains.
Park
Eon Joo
EJ
Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Ogden
Lisa A
LA
Talbot
Amy
A
Evans
Sylvia
S
Cai
Chen-Leng
CL
Black
Brian L
BL
Frank
Deborah U
DU
Moon
Anne M
AM
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D018376:Cardiovascular Abnormalities; D016923:Cell Death; D049109:Cell Proliferation; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006321:Heart / Q000033:anatomy & histology* / Q000196:embryology* / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D060850:LIM-Homeodomain Proteins; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010614:Pharynx / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
D051792:Basic Helix-Loop-Helix Proteins; D051524:Fibroblast Growth Factor 8; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020825:T-Box Domain Proteins; D014157:Transcription Factors; C496457:Fgf8 protein, mouse; C101538:Mesp1 protein, mouse; C491573:Tbx1 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1; C496349:Fgfr1 protein, mouse