Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs

Javier Lopez-Rios, Amandine Duchesne (), Dario Speziale, Guillaume Andrey, Kevin A. Peterson, Philipp Germann, Erkan Ünal, Jing Liu, Sandrine Floriot, Sarah Barbey, Yves Gallard, Magdalena Müller-Gerbl, Andrew D. Courtney, Christophe Klopp, Sabrina Rodriguez, Robert Ivanek, Christian Beisel, Carol Wicking, Dagmar Iber, Benoit Robert, Andrew P. McMahon, Denis Duboule and Rolf Zeller ()
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Javier Lopez-Rios: Developmental Genetics, University of Basel, CH-4058 Basel, Switzerland
Amandine Duchesne: Developmental Genetics, University of Basel, CH-4058 Basel, Switzerland
Dario Speziale: Developmental Genetics, University of Basel, CH-4058 Basel, Switzerland
Guillaume Andrey: School of Life Sciences, Federal Institute of Technology Lausanne, CH-1015 Lausanne, Switzerland
Kevin A. Peterson: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California
Philipp Germann: Federal Institute of Technology Zurich and Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland
Erkan Ünal: Developmental Genetics, University of Basel, CH-4058 Basel, Switzerland
Jing Liu: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California
Sandrine Floriot: Institut National de la Recherche Agronomique, Génétique Animale et Biologie Intégrative, F-78350 Jouy-en-Josas, France
Sarah Barbey: Institut National de la Recherche Agronomique, Domaine Expérimental du Pin au Haras, F-61310 Exmes, France
Yves Gallard: Institut National de la Recherche Agronomique, Domaine Expérimental du Pin au Haras, F-61310 Exmes, France
Magdalena Müller-Gerbl: Institute of Anatomy, University of Basel, CH-4056 Basel, Switzerland
Andrew D. Courtney: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
Christophe Klopp: Institut National de la Recherche Agronomique, Biométrie et Intelligence Artificielle, F-31326 Castanet-Tolosan, France
Sabrina Rodriguez: Institut National de la Recherche Agronomique, Génétique Animale et Biologie Intégrative, F-78350 Jouy-en-Josas, France
Robert Ivanek: Developmental Genetics, University of Basel, CH-4058 Basel, Switzerland
Christian Beisel: Federal Institute of Technology Zurich and Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland
Carol Wicking: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
Dagmar Iber: Federal Institute of Technology Zurich and Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland
Benoit Robert: Institut Pasteur, Génétique Moléculaire de la Morphogenèse and Centre National de la Recherche Scientifique URA-2578, F-75015 Paris, France
Andrew P. McMahon: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California
Denis Duboule: School of Life Sciences, Federal Institute of Technology Lausanne, CH-1015 Lausanne, Switzerland
Rolf Zeller: Developmental Genetics, University of Basel, CH-4058 Basel, Switzerland

Nature, 2014, vol. 511, issue 7507, 46-51

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13289

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