Regular Article
Sonic hedgehogParticipates in Craniofacial Morphogenesis and Is Down-regulated by Teratogenic Doses of Retinoic Acid

https://doi.org/10.1006/dbio.1997.8589Get rights and content
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Abstract

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 instructed to grow, fuse, and differentiate. We undertook a study to determine if the craniofacial primordia used the same molecular cues that mediate growth and patterning in other embryonic tissues such as the neural 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 signalsonic hedghog(shh) and its putative receptor,patched,as well as fibroblast growth factor 8 and bone morphogeneic protein 2.Shh-expressing epithelial grafts functioned 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 processes and thus produce bilateral clefting of the lip and palate, inhibited the expression ofshhandpatchedbut notfgf8,in the craniofacial primordia, and abolished polarizing activity of these tissues. From these studies we 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 retinoids can exert a teratogenic effect on craniofacial morphogenesis independent of its effects on Hox gene expression or neural crest cell migration.

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1

To whom correspondence should be addressed at Department of Orthopaedic Surgery, University of California at San Francisco, U-453, 533 Parnassus Avenue, San Francisco, CA 94143-0514. Fax: (415) 476-1128. E-mail: [email protected].