13-P106 Truncations in primary cilia disrupt Hedgehog/Wnt boundaries in the face

The face is a reflection of our genome. Facial deformities are oftentimes harbingers of an underlying disease states. For example, decreased Hedgehog activity in the developing craniofacial region causes holoprosencephaly and close-set eyes (hypotelorism). We found that excessive Hedgehog activity, caused by truncating the primary cilia on cranial neural crest cells, led to hypertelorism and frontonasal dysplasias (Brugrnann et al., 2009). Here, we show that this loss of the intraflagellar transport protein Kif3a also affects Wnt activity in the face. Using transgenic models to ‘‘map” Wnt activity in the developing face, we found that areas of strong Wnt responsiveness coincided with elevated cell proliferation, which resulted in regionalized outgrowth of the facial prominences. Reducing Wnt signaling, through genetic elimination of Lefl/Tcf4, decreases facial outgrowth but in sharp contrast, deletion of Kif3a in craniofacial mesenchyme resulted in expansion of Wnt responsiveness. The boundaries that form between Hedgehog and Wnt responsiveness were disrupted in the developing face. During Drosophila segmentation Interactions between Hedgehog/Wnt pathways provide instructional cues that establish directionality within an epithelium. Here, we provide evidence that a similar mechanism operates in the embryonic face: our data support a model whereby neural crest cells sense and integrate gradients of Hedgehog and Wnt activity. Disruptions to this Hedgehog/Wnt boundary specification lead to abnormal proliferation in the facial prominences. The resulting phenotype of hypertelorism is a hallmark of numerous craniofacial syndromes, as well as some of the known ciliopathies. These data demonstrate a conserved mechanism whereby patterning and growth is regulated during embryogenesis.