title: Evolution of Hoxa11 regulation in vertebrates is linked to the pentadactyl state.
abstract: The fin-to-limb transition represents one of the major vertebrate morphological innovations associated with the transition from aquatic to terrestrial life and is an attractive model for gaining insights into the mechanisms of morphological diversity between species. One of the characteristic features of limbs is the presence of digits at their extremities. Although most tetrapods have limbs with five digits (pentadactyl limbs), palaeontological data indicate that digits emerged in lobed fins of early tetrapods, which were polydactylous. How the transition to pentadactyl limbs occurred remains unclear. Here we show that the mutually exclusive expression of the mouse genes Hoxa11 and Hoxa13, which were previously proposed to be involved in the origin of the tetrapod limb, is required for the pentadactyl state. We further demonstrate that the exclusion of Hoxa11 from the Hoxa13 domain relies on an enhancer that drives antisense transcription at the Hoxa11 locus after activation by HOXA13 and HOXD13. Finally, we show that the enhancer that drives antisense transcription of the mouse Hoxa11 gene is absent in zebrafish, which, together with the largely overlapping expression of hoxa11 and hoxa13 genes reported in fish, suggests that this enhancer emerged in the course of the fin-to-limb transition. On the basis of the polydactyly that we observed after expression of Hoxa11 in distal limbs, we propose that the evolution of Hoxa11 regulation contributed to the transition from polydactyl limbs in stem-group tetrapods to pentadactyl limbs in extant tetrapods.
authors.affiliation: Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.|Département de Médecine (Programme de Biologie Moléculaire), Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Yacine
authors.initials: Y
authors.lastname: Kherdjemil
authors.affiliation: Department of Biology and CAREG, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Lalonde
authors.affiliation: Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Rushikesh
authors.initials: R
authors.lastname: Sheth
authors.affiliation: Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Dumouchel
authors.affiliation: Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Gemma
authors.initials: G
authors.lastname: de Martino
authors.affiliation: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
authors.forename: Kyriel M
authors.initials: KM
authors.lastname: Pineault
authors.affiliation: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
authors.forename: Deneen M
authors.initials: DM
authors.lastname: Wellik
authors.affiliation: Shriners Hospital for Children, Portland, Oregon 97239, USA.
authors.forename: H Scott
authors.initials: HS
authors.lastname: Stadler
authors.affiliation: Department of Biology and CAREG, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: Marie-Andrée
authors.initials: MA
authors.lastname: Akimenko
authors.affiliation: Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.|Département de Médecine (Programme de Biologie Moléculaire), Université de Montréal, Montréal, Québec H3T 1J4, Canada.|Department of Experimental Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Kmita
mesh_terms: D058500:Animal Fins / Q000033:anatomy & histology / Q000378:metabolism; D000818:Animals; D005075:Biological Evolution; D004742:Enhancer Elements, Genetic / Q000235:genetics; D053476:Extinction, Biological; D005121:Extremities / Q000033:anatomy & histology*; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D007438:Introns / Q000235:genetics; D051379:Mice; D016372:RNA, Antisense / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014714:Vertebrates / Q000033:anatomy & histology* / Q000235:genetics*; D015027:Zebrafish / Q000033:anatomy & histology / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C094041:Hoxa11 protein, mouse; C084118:Hoxd13 protein, mouse; D016372:RNA, Antisense; D014157:Transcription Factors; C099959:homeobox protein HOXA13