The face is a reflection of the remarkable structural diversity that exists throughout the Animal Kingdom. How do these variations in skeletal form arise? We hypothesize that the craniofacial skeleton is patterned by a reiterative series of molecular exchanges between epithelia and mesenchyme, and that Fibroblast growth factors (Fgfs) and Sonic hedgehog are key mediators in this molecular dialogue. Neural crest cells contain species-specific patterning information but the extent to which they regulate patterning in surrounding epithelia is uncertain. In our first series of experiments we will use inter-specific neural crest transplantations and molecular analyses to determine whether neural crest cells influence regional identity of head epithelia. We recently found evidence of such regionalization when we identified a signaling center regulating polarity in the upper beak. In our second set of experiments we will molecular markers to identify putative signaling centers, molecular and cellular analyses to determine the response of neural crest cells to these organizers, and functional assays to ascertain whether these tissues can induce duplications of facial skeletal elements. Two candidate-organizing signals are Fibroblast growth factor 8 (Fgf8) and Sonic hedgehog (Shh). In our third series of experiments we will use a Ioss-of-fucntion approach to determine the role of Fgf8 in facial ectoderm, and distinguish this function from its role in forebrain development. We anticipate that Fgf signaling is required for patterned outgrowth of some facial primordia and for skeletal tissue differentiation. There is growing evidence that Shh primes an embryonic field but does not itself mediate organizer activity. We will test this possibility in our fourth series of experiments using a novel method to inhibit Shh within the plane of the facial ectoderm. Taken together, results from these experiments will provide us with new clues as to how the vertebrate face achieves its extraordinarily intricate pattern.
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