Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate

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.

Reciprocal interactions of Fgf10/Fgfr2b modulate the mouse tongue epithelial differentiation

“…In previous reports, Fgf10 is a major ligand for Fgfr2b, which would govern the development of the skin, hair, and palate (Petiot et al 2003;Rice et al 2004). Fgfr2b, the specific receptor for Fgf7 and Fgf10, is expressed by epithelial cells, thus establishing a stromal-epithelial loop with the mesenchymal Fgf7 and Fgf10 (Eswarakumar et al 2005;Finch et al 1995;Huang et al 2005;Mason et al 1994;Nie et al 2005).…”

Shh signaling is essential for rugae morphogenesis in mice

“…These results confirm that Shh signaling is required for regulation of Ptch1 and Gli1 expression during rugae formation. Epithelial Shh signaling is closely related to the mesenchymal Bmp pathways involved in regulating cell proliferation during palatogenesis (Rice et al 2004;Zhang et al 2002). We observed that only the first palatal ruga was Bmp4 positive after inhibition of Shh signaling by 5E1.…”

“…Fgf and Bmp signaling are regulators of cellular events such as proliferation during palatogenesis and rugae formation (Rice et al 2004;Welsh and O'Brien 2009;Zhang et al 2002). After 5E1 treatment, rugae placode formation was delayed and cell proliferation and apoptosis were disrupted.…”

“…The reciprocal signaling of epithelial-mesenchymal interactions plays a pivotal role in the growth of the secondary palate (Gritli-Linde 2007; Rice et al 2004;Tyler and Koch 1977). Previous studies have shown that epithelial Shh signaling is closely related to both mesenchymal Fgf and Bmp pathways.…”

“…Previous studies have shown that epithelial Shh signaling is closely related to both mesenchymal Fgf and Bmp pathways. These signaling molecules are involved in a cascade regulating cellular events, such as proliferation, during palatogenesis (Rice et al 2004;Sohn et al 2011;Zhang et al 2002). Shh displays a restricted expression pattern in the thickened palatal rugae epithelium regions, which form the transverse ridges on the secondary palate (Bitgood and McMahon 1995).…”