title: Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly.
abstract: Sonic hedgehog (Shh) expression during limb development is crucial for specifying the identity and number of digits. The spatial pattern of Shh expression is restricted to a region called the zone of polarizing activity (ZPA), and this expression is controlled from a long distance by the cis-regulator ZRS. Here, members of two groups of ETS transcription factors are shown to act directly at the ZRS mediating a differential effect on Shh, defining its spatial expression pattern. Occupancy at multiple GABPα/ETS1 sites regulates the position of the ZPA boundary, whereas ETV4/ETV5 binding restricts expression outside the ZPA. The ETS gene family is therefore attributed with specifying the boundaries of the classical ZPA. Two point mutations within the ZRS change the profile of ETS binding and activate Shh expression at an ectopic site in the limb bud. These molecular changes define a pathogenetic mechanism that leads to preaxial polydactyly (PPD).
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lettice
authors.forename: Iain
authors.initials: I
authors.lastname: Williamson
authors.forename: John H
authors.initials: JH
authors.lastname: Wiltshire
authors.forename: Silvia
authors.initials: S
authors.lastname: Peluso
authors.forename: Paul S
authors.initials: PS
authors.lastname: Devenney
authors.forename: Alison E
authors.initials: AE
authors.lastname: Hill
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Essafi
authors.forename: James
authors.initials: J
authors.lastname: Hagman
authors.forename: Richard
authors.initials: R
authors.lastname: Mort
authors.forename: Graeme
authors.initials: G
authors.lastname: Grimes
authors.forename: Carlo L
authors.initials: CL
authors.lastname: DeAngelis
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hill
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D018878:Limb Buds / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation / Q000235:genetics; D017689:Polydactyly / Q000235:genetics*; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050436:Regulatory Elements, Transcriptional; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C494042:Ets1 protein, mouse; C540571:Etv4 protein, mouse; C513242:Etv5 protein, mouse; D051268:GA-Binding Protein Transcription Factor; C495656:Gabpa protein, mouse; D053823:Hedgehog Proteins; D050784:Proto-Oncogene Protein c-ets-1; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; C465570:Shh protein, mouse; D014157:Transcription Factors