title: FGF8 signaling is chemotactic for cardiac neural crest cells.
abstract: Cardiac neural crest cells migrate into the pharyngeal arches where they support development of the pharyngeal arch arteries. The pharyngeal endoderm and ectoderm both express high levels of FGF8. We hypothesized that FGF8 is chemotactic for cardiac crest cells. To begin testing this hypothesis, cardiac crest was explanted for migration assays under various conditions. Cardiac neural crest cells migrated more in response to FGF8. Single cell tracing indicated that this was not due to proliferation and subsequent transwell assays showed that the cells migrate toward an FGF8 source. The migratory response was mediated by FGF receptors (FGFR) 1 and 3 and MAPK/ERK intracellular signaling. To test whether FGF8 is chemokinetic and/or chemotactic in vivo, dominant negative FGFR1 was electroporated into the premigratory cardiac neural crest. Cells expressing the dominant negative receptor migrated slower than normal cardiac neural crest cells and were prone to remain in the vicinity of the neural tube and die. Treating with the FGFR1 inhibitor, SU5402 or an FGFR3 function-blocking antibody also slowed neural crest migration. FGF8 over-signaling enhanced neural crest migration. Neural crest cells migrated to an FGF8-soaked bead placed dorsal to the pharynx. Finally, an FGF8 producing plasmid was electroporated into an ectopic site in the ventral pharyngeal endoderm. The FGF8 producing cells attracted a thick layer of mesenchymal cells. DiI labeling of the neural crest as well as quail-to-chick neural crest chimeras showed that neural crest cells migrated to and around the ectopic site of FGF8 expression. These results showing that FGF8 is chemotactic and chemokinetic for cardiac neural crest adds another dimension to understanding the relationship of FGF8 and cardiac neural crest in cardiovascular defects.
authors.affiliation: Department of Pediatrics (Neonatology), Duke University, Durham, NC 27710, USA.
authors.forename: Asako
authors.initials: A
authors.lastname: Sato
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Scholl
authors.forename: E N
authors.initials: EN
authors.lastname: Kuhn
authors.forename: E B
authors.initials: EB
authors.lastname: Kuhn
authors.forename: Harriett A
authors.initials: HA
authors.lastname: Stadt
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Decker
authors.forename: Kelly
authors.initials: K
authors.lastname: Pegram
authors.forename: Mary R
authors.initials: MR
authors.lastname: Hutson
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Kirby
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000196:embryology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010614:Pharynx / Q000196:embryology / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D011758:Pyrroles; C105686:SU 5402; C113580:U 0126; D049452:Green Fluorescent Proteins; D051524:Fibroblast Growth Factor 8; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases