The role of Sonic hedgehog in normal and abnormal craniofacial morphogenesis

There is growing evidence that implicates a role for Sonic hedgehog (SHH) i n morphogenesis of the craniofacial complex. Mutations in human and murine SHH cause midline patterning defects that are manifested in the head as hol oprosencephaly and cyclopia, In addition, teratogens such as jervine, which inhibit the response of tissues to SHH, also produce cyclopia. Thus, the l oss of SHH signaling during early stages of neural plate patterning has a p rofound influence of craniofacial morphogenesis. However, the severity of t hese defects precludes analyses of SHH function during later stages of cran iofacial development. We have used an embryonic chick system to study the r ole of SHH during these later stages of craniofacial development. Using a c ombination of surgical and molecular experiments, we show here that SHH is essential for morphogenesis of the frontonasal and maxillary processes (FNP and MXPs), which give rise to the mid- and upper face, Transient loss of S HH signaling in the embryonic face inhibits growth of the primordia and res ults in defects analogous to hypotelorism and cleft lip/palate, characteris tics of the mild forms of holoprosencephaly, In contrast, excess SHH leads to a mediolateral widening of the FNP and a widening between the eyes, a co ndition known as hypertelorism. In severe cases, this widening is accompani ed by facial duplications. Collectively, these experiments demonstrate that SHH has multiple and profound effects on the entire spectrum of craniofaci al development, and perturbations in SHH signaling are likely to underlie a number of human craniofacial anomalies.