The alx gene family confers segmental identity to frontonasal cranial neural crest cells

Cranial neural crest cells in the pharyngeal arches give rise to vertebrate head skeletal structures. Hox genes confer segmental identity to the different arches, and Hox mutations result in mirror-image homeotic duplications. Frontonasal cranial neural crest cells reside anterior to the first pharyngeal arch, give rise to the midface skeleton, and are not considered part of the segmental series. Here, we demonstrate that alx genes confer segmental identity to this anterior-most population in zebrafish; alx mutations result in mirror-image homeotic transformations. We define the boundary between the frontonasal and arch populations and demonstrate that Alx expression is restricted to the anterior-most cranial neural crest cells in zebrafish and lamprey, suggesting these expression patterns were present early in the vertebrate lineage. We propose that frontonasal neural crest cells represent the anterior-most segment of the pharyngeal arch meristic series, and that Alx genes function as homeotic selector genes conferring their segmental identity. Here they show homeotic transformation of the frontonasal region to upper jaw identity in zebrafish alx mutants. These findings revive a debated, historical theory of vertebrate head segmentation where the anterior-most region is segmentally homologous with the pharyngeal arches.