Facial development occurs through the outgrowth and fusion of neural crest-derived facial prominences that surround the primitive oral cavity. Failure of the prominences to grow together properly can result in a number of facial deformities, of which cleft lip with or without cleft palate is the most common. A mutation known as cleft primary palate (cpp) has been discovered in the chicken that causes complete failure of outgrowth of the upper facial prominences with the consequence that a

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... ral cleft lip is formed. A series of grafting experiments showed that the mutation affects the frontonasal mass but not other facial prominences. Recombination experiments showed the growth of cpp mutant frontonasal mass mesenchyme is restored by recombination with wild-type epithelium. In contrast, the growth of normal craniofacial mesenchyme is not supported by cpp mutant frontonasal mass epithelium, implying that the mutation primarily affects the epithelium and not the mesenchyme. The failure of outgrowth is not due to a lack of skeletogenesis, since cartilage forms in all grafts containing cpp mutant tissue. Fgf8, which is usually restricted to the epithelium surrounding the nasal pits, was found throughout the frontonasal mass epithelium of stage 24 and 28 cpp mutant embryos. Expression of other genes localized to the frontonasal mass epithelium (Bmp4, Noggin and Shh) or in the frontonasal mass mesenchyme (Patched-1, Msxl, Msx2, AP2, type II collagen) was the same as in normal embryos. Programmed cell death in the cpp mutant frontonasal mass also did not differ from the normal. Cell proliferation, however, was increased in the mesenchyme underlying the ectopic Fgf8-expressing epithelium, leading to growth along the cranio-caudal rather than the proximo-distal axis. These results indicate that the failure of the cpp frontonasal mass to grow along a proximo-distal axis is due to a signalling defect in the epithelium. The cpp mutation is upstream of Fgf8, and ectopic Fgf8 expression may lead to th [...]