title: Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model.
abstract: Apert syndrome (AS) is a severe congenital disease caused by mutations in fibroblast growth factor receptor-2 (FGFR2), and characterised by craniofacial, limb, visceral, and neural abnormalities. AS-type FGFR2 molecules exert a gain-of-function effect in a ligand-dependent manner, but the causative FGFs and their relative contribution to each of the abnormalities observed in AS remains unknown. We have generated mice that harbour an AS mutation but are deficient in or heterozygous for Fgf10. The genetic knockdown of Fgf10 can rescue the skeletal as well as some of the visceral defects observed in this AS model, and restore a near normal level of FgfR2 signaling involving an apparent switch between ERK(p44/p42) and p38 phosphorylation. Surprisingly, it can also yield de novo cleft palate and blind colon in a subset of the compound mutants. These findings strongly suggest that Fgf10 contributes to AS-like pathologies and highlight a complexity of Fgf10 function in different tissues.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich, United Kingdom. m.k.h@uea.ac.uk
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Hajihosseini
authors.forename: Raquel
authors.initials: R
authors.lastname: Duarte
authors.forename: Jean
authors.initials: J
authors.lastname: Pegrum
authors.forename: Anne
authors.initials: A
authors.lastname: Donjacour
authors.forename: Eva
authors.initials: E
authors.lastname: Lana-Elola
authors.forename: David P
authors.initials: DP
authors.lastname: Rice
authors.forename: James
authors.initials: J
authors.lastname: Sharpe
authors.forename: Clive
authors.initials: C
authors.lastname: Dickson
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D002972:Cleft Palate / Q000235:genetics; D003106:Colon / Q000002:abnormalities; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D008168:Lung / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010766:Phosphorylation; D020033:Protein Isoforms / Q000096:biosynthesis; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction; D014781:Viscera / Q000002:abnormalities*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D020033:Protein Isoforms; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases