Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.
Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10-/-, FGF receptor 2b-/- (Fgfr2b-/-), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b-/- mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network.
Rice
Ritva
R
Departments of Craniofacial Development and Orthodontics, King's College, London, United Kingdom.
Spencer-Dene
Bradley
B
Connor
Elaine C
EC
Gritli-Linde
Amel
A
McMahon
Andrew P
AP
Dickson
Clive
C
Thesleff
Irma
I
Rice
David P C
DP
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002972:Cleft Palate / Q000209:etiology / Q000378:metabolism*; D046508:Culture Techniques; D004848:Epithelium / Q000502:physiology*; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010159:Palate / Q000166:cytology / Q000196:embryology*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
C496464:Fgf10 protein, mouse; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D053823:Hedgehog Proteins; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C465570:Shh protein, mouse; D015534:Trans-Activators; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D051497:Receptor, Fibroblast Growth Factor, Type 2