Development of the lip and palate: FGF signalling.

The fibroblast growth factor (FGF) signalling pathway is critically involved in several aspects of craniofacial development, including formation of the lip and the palate. FGF receptors are activated by extracellular FGF ligands in order to regulate cellular processes such as migration and morphogenesis through instruction of specific target gene expression. A key factor in the development of orofacial structures is the interaction between mesodermal- and neural crest-derived mesenchyme and ecto- and endodermal-derived epithelium. FGF signalling occurs in both cell types and promotes epithelial-mesenchymal communication through region-specific expression of receptor subtypes. Many FGF ligands and receptors are expressed at specific stages and at precise locations during normal palatogenesis and an absolute requirement of some has been demonstrated by their (conditional) inactivation resulting in a cleft palate phenotype. Other important signalling pathways involving SHH and SPRY are intricately involved in the interpretation of FGF signalling. As a cause of human pathology, functionally validated FGF pathway gene mutations have been exclusively associated with syndromic forms of cleft lip and palate. Most commonly, this includes patients with mutations in FGFR1 and FGFR2 (Kallmann, Pfeiffer, Apert and Crouzon syndromes) where cleft palate is part of a broad craniofacial phenotype, including craniosynostosis. Similarly, FGF8 mutations have been found in patients with Kallmann-like idiopathic hypogonadotropic hypogonadism, some also with cleft lip and palate. In this chapter, we will provide an overview of the relevant FGF ligands and receptors important for lip and palate morphogenesis, correlating their expression patterns with the effects of their perturbation that lead to a clefting pathogenesis.