title: Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs.
abstract: The large spectrum of limb morphologies reflects the wide evolutionary diversification of the basic pentadactyl pattern in tetrapods. In even-toed ungulates (artiodactyls, including cattle), limbs are adapted for running as a consequence of progressive reduction of their distal skeleton to symmetrical and elongated middle digits with hoofed phalanges. Here we analyse bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded SHH signalling during bovine handplate development. Our study provides a molecular explanation for the loss of digit asymmetry in bovine limb buds and suggests that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs.
authors.affiliation: 1] Developmental Genetics, Department Biomedicine, University of Basel, CH-4058 Basel, Switzerland [2].
authors.forename: Javier
authors.initials: J
authors.lastname: Lopez-Rios
authors.affiliation: 1] Developmental Genetics, Department Biomedicine, University of Basel, CH-4058 Basel, Switzerland [2] Institut National de la Recherche Agronomique, Génétique Animale et Biologie Intégrative, F-78350 Jouy-en-Josas, France [3].
authors.forename: Amandine
authors.initials: A
authors.lastname: Duchesne
authors.affiliation: Developmental Genetics, Department Biomedicine, University of Basel, CH-4058 Basel, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Speziale
authors.affiliation: School of Life Sciences, Federal Institute of Technology Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Andrey
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Peterson
authors.affiliation: Department for Biosystems Science and Engineering, Federal Institute of Technology Zurich and Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Germann
authors.affiliation: 1] Developmental Genetics, Department Biomedicine, University of Basel, CH-4058 Basel, Switzerland [2] Department for Biosystems Science and Engineering, Federal Institute of Technology Zurich and Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland.
authors.forename: Erkan
authors.initials: E
authors.lastname: Unal
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institut National de la Recherche Agronomique, Génétique Animale et Biologie Intégrative, F-78350 Jouy-en-Josas, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Floriot
authors.affiliation: Institut National de la Recherche Agronomique, Domaine Expérimental du Pin au Haras, F-61310 Exmes, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Barbey
authors.affiliation: Institut National de la Recherche Agronomique, Domaine Expérimental du Pin au Haras, F-61310 Exmes, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Gallard
authors.affiliation: Institute of Anatomy, Department Biomedicine, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Müller-Gerbl
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Courtney
authors.affiliation: Institut National de la Recherche Agronomique, Biométrie et Intelligence Artificielle, F-31326 Castanet-Tolosan, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Klopp
authors.affiliation: 1] Institut National de la Recherche Agronomique, Génétique Animale et Biologie Intégrative, F-78350 Jouy-en-Josas, France [2] Institut National de la Recherche Agronomique, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, F-31077 Toulouse, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: 1] Developmental Genetics, Department Biomedicine, University of Basel, CH-4058 Basel, Switzerland [2] Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Ivanek
authors.affiliation: Department for Biosystems Science and Engineering, Federal Institute of Technology Zurich and Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Beisel
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Wicking
authors.affiliation: Department for Biosystems Science and Engineering, Federal Institute of Technology Zurich and Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Iber
authors.affiliation: Institut Pasteur, Génétique Moléculaire de la Morphogenèse and Centre National de la Recherche Scientifique URA-2578, F-75015 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Robert
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.affiliation: 1] School of Life Sciences, Federal Institute of Technology Lausanne, CH-1015 Lausanne, Switzerland [2] Department of Genetics and Evolution, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Duboule
authors.affiliation: Developmental Genetics, Department Biomedicine, University of Basel, CH-4058 Basel, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Zeller
mesh_terms: D000818:Animals; D005075:Biological Evolution; D019521:Body Patterning; D002417:Cattle; D005121:Extremities / Q000033:anatomy & histology* / Q000196:embryology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D018878:Limb Buds / Q000033:anatomy & histology / Q000196:embryology; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface