title: Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals.
abstract: Evolutionary change in gene regulation can result from changes in cis-regulatory elements, leading to differences in the temporal and spatial expression of genes or in the coding region of transcription factors leading to novel functions or both. Although there is a growing body of evidence supporting the importance of cis-regulatory evolution, examples of protein-mediated evolution of novel developmental pathways have not been demonstrated. Here, we investigate the evolution of prolactin (PRL) expression in endometrial cells, which is essential for placentation/pregnancy in eutherian mammals and is a direct regulatory target of the transcription factor HoxA-11. Here, we show that (i) endometrial PRL expression is a derived feature of placental mammals, (ii) the PRL regulatory gene HoxA-11 experienced a period of strong positive selection in the stem-lineage of eutherian mammals, and (iii) only HoxA-11 proteins from placental mammals, including the reconstructed ancestral eutherian gene, are able to up-regulate PRL from the promoter used in endometrial cells. In contrast, HoxA-11 from the reconstructed therian ancestor, opossum, platypus, and chicken are unable to up-regulate PRL expression. These results demonstrate that the evolution of novel gene expression domains is not only mediated by the evolution of cis-regulatory elements but can also require evolutionary changes of transcription factor proteins themselves.
authors.affiliation: Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA. vincent.j.lynch@yale.edu
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Lynch
authors.forename: Andrea
authors.initials: A
authors.lastname: Tanzer
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wang
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Leung
authors.forename: Birgit
authors.initials: B
authors.lastname: Gellersen
authors.forename: Deena
authors.initials: D
authors.lastname: Emera
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Wagner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens / Q000235:genetics / Q000378:metabolism; D004606:Elephants / Q000235:genetics / Q000378:metabolism; D004717:Endometrium / Q000378:metabolism*; D019143:Evolution, Molecular; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009893:Opossums / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy / Q000235:genetics*; D011388:Prolactin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012641:Selection, Genetic
chemical_list: C484298:HOXA11 protein, human; D018398:Homeodomain Proteins; D011388:Prolactin