The mammalian Crx genes are highly divergent representatives of the Otx5 gene family, a gnathostome orthology class of orthodenticle-related homeogenes involved in the differentiation of retinal photoreceptors and circadian entrainment.

The mammalian Crx genes are highly divergent orthodenticle (otd)-related homeogenes that play important roles in the differentiation of retinal photoreceptors and the circadian entrainment. However, their evolutionary origin and orthological relationships with other otd-related genes remain unclear. An orthology relationship of these genes with the highly conserved Otx5 genes identified in fish and amphibians, and also expressed in the eye and epiphysis, has been proposed previously but remains controversial. To test this hypothesis, we have identified Crx genes in a wide range of mammals, including three marsupials, and Otx5-related genes in a lizard, a turtle, and two archosaurs (crocodile and chick), as well as in the pufferfish. Phylogenetic analyses of the coding sequences show that the mammalian Crx genes are orthologous to the Otx5-related genes isolated in other gnathostomes. They also indicate that a duplication event has taken place in actinopterygians, after the splitting of the Cladistia, and that a relaxation of the structural constraints acting on the gene coding region has occurred early in the mammalian lineage. This process may be linked not only to the loss of ancestral Otx5/Crx functions during gastrulation or in the retinal pigmented epithelium, but also to the evolution of photic entrainment mechanisms in mammals.