Prx1 and Prx2 are upstream regulators of sonic hedgehog and control cell proliferation during mandibular arch morphogenesis

The aristaless-related homeobox genes Prx1 and Prx2 are required for correc t skeletogenesis in many structures. Mice that lack both Prx1 and Prx2 func tions display reduction or absence of skeletal elements in the skull, face, limbs and vertebral column. A striking phenotype is found in the lower jaw , which shows loss of midline structures, and the presence of a single, med ially located incisor. We investigated development of the mandibular arch o f Prx1(-/-)Prx2(-/-) mutants to obtain insight into the molecular basis of the lower jaw abnormalities. We observed in mutant embryos a local decrease in proliferation of mandibular arch mesenchyme in a medial area. Interesti ngly, in the oral epithelium adjacent to this mesenchyme, sonic hedgehog (S hh) expression was strongly reduced, indicative of a function for Prx genes in indirect regulation of Shh. Wild-type embryos that were exposed to the hedgehog-pathway inhibitor, jervine, partially phenocopied the lower jaw de fects of Prx1(-/-)Prx2(-/-) mutants. In addition, this treatment led to los s of the mandibular incisors. We present a model that describes how loss of Shh expression in Prx1(-/-)Prx2(-/-) mutants leads to abnormal morphogenes is of the mandibular arch.