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A group of mouse aristaless-related genes has been implicated in functions in the development of the craniofacial skeleton. We have generated an Alx3 mutant allele in which the lacZ coding sequence is inserted in-frame in the Alx3 gene and the sequences encoding the conserved protein domains are deleted. Mice homozygous for this null allele are indistinguishable from wild-type mice. Compound mutants of Alx3 and Alx4, however, show severe craniofacial abnormalities that are absent in Alx4 single mutants. Alx3/Alx4 double mutant newborn mice have cleft nasal regions. Most facial bones and many other neural crest derived skull elements are malformed, truncated or even absent. The craniofacial defects in Alx3/Alx4 double mutant embryos become anatomically manifest around embryonic day 10.5, when the nasal processes appear to be abnormally positioned. This most probably leads to a failure of the medial nasal processes to fuse in the facial midline and subsequently to the split face phenotype. We detected a significant increase in apoptosis localised in the outgrowing frontonasal process in embryonic day 10.0 double mutant embryos, which we propose to be the underlying cause of the subsequent malformations.

The aristaless-related homeobox genes Prx1 and Prx2 are required for correct skeletogenesis in many structures. Mice that lack both Prx1 and Prx2 functions 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, medially located incisor. We investigated development of the mandibular arch of 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. Interestingly, in the oral epithelium adjacent to this mesenchyme, sonic hedgehog (Shh) 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 defects of Prx1(-/-)Prx2(-/-) mutants. In addition, this treatment led to loss of the mandibular incisors. We present a model that describes how loss of Shh expression in Prx1(-/-)Prx2(-/-) mutants leads to abnormal morphogenesis of the mandibular arch.