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In order to improve our understanding of melatonin signaling, we have reviewed and revised the evolutionary history of melatonin receptor genes ( mtnr ) in vertebrates. All gnathostome  mtnr genes  have a conserved gene organization with two exons, except for  mtnr1b  paralogs of some teleosts that show intron gains. Phylogeny and synteny analyses demonstrate the presence of four  mtnr  subtypes, MTNR1A, MTNR1B, MTNR1C, MTNR1D that arose from duplication of an ancestral  mtnr  during the vertebrate tetraploidizations (1R and 2R). In tetrapods,  mtnr1d  was lost, independently, in mammals, in archosaurs and in caecilian amphibians. All four  mtnr  subtypes were found in two non-teleost actinopterygian species, the spotted gar and the reedfish. As a result of teleost tetraploidization (3R), up to seven functional  mtnr  genes could be identified in teleosts. Conservation of the  mtnr  3R-duplicated paralogs differs among the teleost lineages. Synteny analysis showed that the  mtnr1d  was conserved as a singleton in all teleosts resulting from an early loss after tetraploidization of one of the teleost 3R and salmonid 4R paralogs. Several teleosts including the eels and the piranha have conserved both 3R-paralogs of  mtnr1a, mtnr1b , and  mtnr1c . Loss of one of the 3R-paralogs depends on the lineage:  mtnr1ca  was lost in euteleosts whereas  mtnr1cb  was lost in osteoglossomorphs and several ostariophysians including the zebrafish. We investigated the tissue distribution of  mtnr  expression in a large range of tissues in medaka. The medaka has conserved the four vertebrate paralogs, and these are expressed in brain and retina, and, differentially, in peripheral tissues. Photoperiod affects  mtnr  expression levels in a gene-specific and tissue-specific manner. This study provides new insights into the repertoire diversification and functional evolution of the  mtnr  gene family in vertebrates.

New Insights Into the Evolutionary History of Melatonin Receptors in Vertebrates, With Particular Focus on Teleosts