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Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate
Ritva Rice, … , Irma Thesleff, David P.C. Rice
Ritva Rice, … , Irma Thesleff, David P.C. Rice
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1692-1700. https://doi.org/10.1172/JCI20384.
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Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate

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Abstract

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.

Authors

Ritva Rice, Bradley Spencer-Dene, Elaine C. Connor, Amel Gritli-Linde, Andrew P. McMahon, Clive Dickson, Irma Thesleff, David P.C. Rice

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Figure 5

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Shh is a target of Fgf10/Fgfr2b signaling. (A) FGF10-impregnated bead st...
Shh is a target of Fgf10/Fgfr2b signaling. (A) FGF10-impregnated bead stimulates palatal epithelial proliferation (arrow). (B) BSA-impregnated bead had no effect on proliferation. (C) Shh bead stimulated proliferation in isolated palatal mesenchymal explants. (D) FGF10 induced Shh in vitro, in the oral side of WT palatal epithelium (arrow), but not in Fgfr2b_/_ mutant mice (E). (F) FGF10 also induced Ptc1 in the mesenchyme immediately adjacent to the bead in palatal explants (arrows). Ptc1 is a known target of Shh and an indicator of the level of hedgehog signaling. (G_L) In situ hybridization to detect Shh mRNA. Shh was expressed in the MEE and the oral side of the palatal epithelium, as well as in the dorsum of the tongue. (H, I, K, and L) In Fgfr2b_/_ and Fgf10_/_ mutants, Shh expression was reduced and concentrated to discrete patches of palatal epithelium. Shh remained expressed throughout the tongue dorsum epithelium (arrow). (M and N) Frontal histological sections through the posterior oral region of NB WT (M) and K14-Cre;Shhc/n (N) mice, stained with Ladewig’s trichrome. (M) In the WT mouse, the palatal shelves had elevated and fused in the midline forming a barrier between the oral cavity and the nasopharynx (asterisk). (N) The palatal shelves of K14-Cre;Shhc/n mutants failed to develop beyond rudimentary processes. (O) In situ hybridization to detect Smo mRNA at E13. Transcripts were detected in the mesenchyme of the palate (arrow). G_I, L and O, same magnification; scale bars: 200 ∝m. J and K: original magnification, ∞12.5.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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