The Roles of Hedgehog Signaling in Upper Lip Formation

Abstract

Craniofacial development consists of a highly complex sequence of the orchestrated growth and fusion of facial processes. It is also known that craniofacial abnormalities can be detected in 1/3 of all patients with congenital diseases. Within the various craniofacial abnormalities, orofacial clefting is one of the most common phenotypic outcomes associated with retarded facial growth or fusion. Cleft lip is one of the representative and frequently encountered conditions in the spectrum of orofacial clefting. Despite various mechanisms or signaling pathways that have been proposed to be the cause of cleft lip, a detailed mechanism that bridges individual signaling pathways to the cleft lip is still elusive. Shh signaling is indispensable for normal embryonic development, and disruption can result in a wide spectrum of craniofacial disorders, including cleft lip. This review focuses on the current knowledge about the mechanisms of facial development and the etiology of cleft lip that are related to Shh signaling.

Figure 1

The growth of facial processes in mouse embryos shown by whole mount nuclear fluorescent imaging. ((A)–(E)) Oblique views of the facial development of mouse embryos from E10 to E12.0. ((F)–(J)) The same heads were captured from the ventral side of the head with the mandible removed. (K) The representative phenotype of cleft lip, which was induced by whole embryo culture. The red arrowheads show the position where the facial processes fuse. (L) Cartoon sequence of growing nasal processes at each stage. Black arrow shows the direction of processes growth and folding. MNP: medial nasal process, LNP: lateral nasal process, MXP: maxillary process, and Mn; mandible.

Figure 2

The expression of Shh and Patched1 during the growth of facial processes in mouse embryos. ((a), (c), and (e)) In situ hybridization of Shh on E10 and E11.0. (b) In situ hybridization of Patched1 on E10. ((d) and (f)) LacZ staining of E11.0 Patched1-LacZ mice. (g) LacZ staining of a Topgal mouse embryo on E11.0. The red arrowheads indicate the position of the frontonasal ectodermal zone (FEZ).