Meeting Abstract

20.2  Thursday, Jan. 3  Novel functional specificity of HoxA-11 evolves through changes in the transcription factor protein. LYNCH, Vincent/J*; WAGNER, Gunter/P; Yale University; Yale University vincent.j.lynch@yale.edu

The evolution of morphological characters is mediated by the evolution of gene regulation. While there is broad agreement for the importance of cis-regulatory evolution, it has only recently been shown that transcription factors may not remain functionally equivalent during evolution, suggesting that changes in transcription factor functions can contribute to the evolution of morphological characters and the origination of molecular and developmental novelties. Convincing examples of transcription factors acquiring novel functions, however, remain elusive. Here we show that a Hox gene (HoxA-11) essential for the development and function of the female reproductive tract in placental mammals experienced a strong episode of adaptive amino acid change in the common ancestor of placental mammals coincident with the origin of invasive placentation. Our functional studies show that HoxA-11 is required for the expression of downstream target genes that are vital for uterine function, and directly regulates the expression of prolactin (PRL) in endometrial stromal cells by forming an enhancesome with other transcription factors known to be essential for decidual prolactin expression. Remarkably, only HoxA-11 from placental mammals (human and mouse) is able to activate transcription from the prolactin promoter, while non-placental mammal (opossum, platypus) and reptile (chicken) genes cannot. These adaptive, placental-mammal specific, changes in HoxA-11 recruited it into a new gene regulation network enabling HoxA-11 to silence the expression of genes detrimental to pregnancy. We conclude that changes in transcription factors proteins are essential for the evolution of novel functional specificities in gene regulation.