Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model.
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.
Hajihosseini
Mohammad K
MK
School of Biological Sciences, University of East Anglia, Norwich, United Kingdom. m.k.h@uea.ac.uk
Duarte
Raquel
R
Pegrum
Jean
J
Donjacour
Anne
A
Lana-Elola
Eva
E
Rice
David P
DP
Sharpe
James
J
Dickson
Clive
C
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
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