SONIC HEDGEHOG PARTICIPATES IN CRANIOFACIAL MORPHOGENESIS AND IS DOWN-REGULATED BY TERATOGENIC DOSES OF RETINOIC ACID

The face is one of the most intricately patterned structures in human and yet little is known of the mechanisms by which the tissues are ins tructed to grow, fuse, and differentiate. We undertook a study to dete rmine if the craniofacial primordia used the same molecular cues that mediate growth and patterning in other embryonic tissues such as the n eural tube and the limb. Here we provide evidence for the presence of organizer-like tissues in the craniofacial primordia. These candidate organizers express the polarizing signal sonic hedghog (shh) and its p utative receptor, patched, as well as fibroblast growth factor 8 and b one morphogeneic protein 2. Shh-expressing epithelial grafts functione d as organizing tissues in a limb bud assay system, where they evoked duplications of the digit pattern. High doses of retinoic acid, which are known to truncate the growth of the frontonasal and maxillary proc esses and thus produce bilateral clefting of the lip and palate, inhib ited the expression of shh and patched but not fgf8, in the craniofaci al primordia, and abolished polarizing activity of these tissues. from these studies rye conclude that the embryonic face contains signaling centers in the epithelium that participate in craniofacial growth and patterning. In addition, we discuss a novel mechanism whereby retinoi ds can exert a teratogenic effect on craniofacial morphogenesis indepe ndent of its effects on Hox gene expression or neural crest cell migra tion. (C) 1997 Academic Press.