title: Evolving Hox activity profiles govern diversity in locomotor systems.
abstract: The emergence of limb-driven locomotor behaviors was a key event in the evolution of vertebrates and fostered the transition from aquatic to terrestrial life. We show that the generation of limb-projecting lateral motor column (LMC) neurons in mice relies on a transcriptional autoregulatory module initiated via transient activity of multiple genes within the HoxA and HoxC clusters. Repression of this module at thoracic levels restricts expression of LMC determinants, thus dictating LMC position relative to the limbs. This suppression is mediated by a key regulatory domain that is specifically found in the Hoxc9 proteins of appendage-bearing vertebrates. The profile of Hoxc9 expression inversely correlates with LMC position in land vertebrates and likely accounts for the absence of LMC neurons in limbless species such as snakes. Thus, modulation of both Hoxc9 protein function and Hoxc9 gene expression likely contributed to evolutionary transitions between undulatory and ambulatory motor circuit connectivity programs.
authors.affiliation: Howard Hughes Medical Institute, NYU Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Jung
authors.affiliation: Department of Biology, New York University, New York, NY 10003, USA.
authors.forename: Esteban O
authors.initials: EO
authors.lastname: Mazzoni
authors.affiliation: Department of Genetics and Evolution, University of Geneva, Sciences III, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland; Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Soshnikova
authors.affiliation: Howard Hughes Medical Institute, NYU Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Hanley
authors.affiliation: Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Byrappa
authors.initials: B
authors.lastname: Venkatesh
authors.affiliation: Department of Genetics and Evolution, University of Geneva, Sciences III, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale, 1015 Lausanne, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Duboule
authors.affiliation: Howard Hughes Medical Institute, NYU Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: jeremy.dasen@nyumc.org.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Dasen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens; D019143:Evolution, Molecular; D051858:Forkhead Transcription Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox / Q000235:genetics / Q000502:physiology*; D014644:Genetic Variation; D018398:Homeodomain Proteins / Q000235:genetics; D008116:Lizards; D008124:Locomotion / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics; D012911:Snakes; D014714:Vertebrates / Q000196:embryology / Q000235:genetics* / Q000502:physiology*
chemical_list: D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D018398:Homeodomain Proteins; C065404:Hoxc9 protein, mouse; D012097:Repressor Proteins
references.citation: Neuron. 2008 Jul 31;59(2):226-40
references.pmid: 18667151
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10682-6
references.pmid: 23674686
references.citation: Curr Top Dev Biol. 2009;88:169-200
references.pmid: 19651305
references.citation: Neuron. 2004 May 13;42(3):375-86
references.pmid: 15134635
references.citation: Cell. 2005 Nov 4;123(3):477-91
references.pmid: 16269338
references.citation: Nature. 2005 Jun 23;435(7045):1113-6
references.pmid: 15973411
references.citation: Nature. 2003 Oct 30;425(6961):917-25
references.pmid: 14586460
references.citation: Curr Opin Neurobiol. 2012 Aug;22(4):615-23
references.pmid: 22417941
references.citation: Nature. 2002 Feb 21;415(6874):914-7
references.pmid: 11859370
references.citation: Nature. 2002 Apr 4;416(6880):527-31
references.pmid: 11932743
references.citation: Neuron. 2001 Dec 20;32(6):997-1012
references.pmid: 11754833
references.citation: PLoS Genet. 2013;9(1):e1003184
references.pmid: 23359544
references.citation: Curr Opin Genet Dev. 2002 Oct;12(5):558-64
references.pmid: 12200161
references.citation: Development. 2005 Apr;132(7):1611-21
references.pmid: 15753214
references.citation: Development. 2008 Jan;135(1):171-82
references.pmid: 18065432
references.citation: Curr Opin Neurobiol. 2009 Dec;19(6):572-86
references.pmid: 19896834
references.citation: Nature. 1996 Dec 19-26;384(6610):630-4
references.pmid: 8967950
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5720-4
references.pmid: 19321424
references.citation: Science. 2011 Dec 16;334(6062):1517
references.pmid: 22174244
references.citation: Dev Biol. 2000 Apr 15;220(2):333-42
references.pmid: 10753520
references.citation: Development. 2001 Aug;128(16):3081-94
references.pmid: 11688558
references.citation: Eur J Neurosci. 2001 Nov;14(10):1727-38
references.pmid: 11860467
references.citation: Dev Dyn. 2004 Sep;231(1):43-56
references.pmid: 15305286
references.citation: Cell. 1994 Dec 16;79(6):957-70
references.pmid: 7528105
references.citation: Nature. 2002 Feb 21;415(6874):910-3
references.pmid: 11859369
references.citation: Neuron. 2010 Sep 9;67(5):781-96
references.pmid: 20826310
references.citation: Nature. 2012 Aug 30;488(7413):642-6
references.pmid: 22932389
references.citation: Nat Commun. 2010 Jul 27;1:49
references.pmid: 20975699
references.citation: EMBO J. 1997 Jun 2;16(11):3145-57
references.pmid: 9214632
references.citation: J Neurophysiol. 1978 Jan;41(1):97-107
references.pmid: 621549
references.citation: Brain Behav Evol. 1992;40(2-3):82-97
references.pmid: 1422809
references.citation: Nature. 2003 Oct 30;425(6961):926-33
references.pmid: 14586461
references.citation: Integr Comp Biol. 2013 Aug;53(2):283-94
references.pmid: 23667046
references.citation: Development. 1995 Feb;121(2):333-46
references.pmid: 7768176
references.citation: Dev Cell. 2010 Apr 20;18(4):655-61
references.pmid: 20412779
references.citation: Nature. 2006 Aug 31;442(7106):1033-7
references.pmid: 16878142
references.citation: Nature. 1999 Jun 3;399(6735):474-9
references.pmid: 10365960
references.citation: Cell. 1998 Aug 21;94(4):503-14
references.pmid: 9727493
references.citation: Development. 2007 Aug;134(16):2981-9
references.pmid: 17626057
references.citation: Cell. 2008 Jul 25;134(2):304-16
references.pmid: 18662545
references.citation: Evol Dev. 2012 Sep-Oct;14(5):412-20
references.pmid: 22947314
references.citation: J Neurosci. 1996 Sep 15;16(18):5777-94
references.pmid: 8795632
references.citation: Neuron. 2013 Oct 2;80(1):12-34
references.pmid: 24094100
references.citation: Genes Dev. 2012 Oct 1;26(19):2236-50
references.pmid: 23028147
references.citation: Development. 2004 Sep;131(18):4477-87
references.pmid: 15342473
references.citation: Dev Biol. 2011 Jul 1;355(1):164-72
references.pmid: 21540022
references.citation: Nucleic Acids Res. 2002 Jun 15;30(12):2663-8
references.pmid: 12060683
references.citation: EMBO J. 1991 Aug;10(8):2279-89
references.pmid: 1676674
references.citation: Int J Dev Neurosci. 2001 Apr;19(2):175-82
references.pmid: 11255031
references.citation: Nature. 2006 Apr 6;440(7085):757-63
references.pmid: 16598249
references.citation: Brain Res. 1983 Oct 16;276(2):201-11
references.pmid: 6627006