Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly

Laura A Lettice, Iain Williamson, John H Wiltshire, Silvia Peluso, Paul S Devenney, Alison E Hill, Abdelkader Essafi, James Hagman, Richard Mort, Graeme Grimes, Carlo L DeAngelis, Robert E Hill

Research output: Contribution to journalArticle (Academic Journal)

88 Citations (Scopus)


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).
Original languageEnglish
Pages (from-to)459-467
Number of pages9
JournalDevelopmental Cell
Issue number2
Publication statusPublished - 14 Feb 2012


Bibliographical note

Copyright © 2012 Elsevier Inc. All rights reserved.


  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins
  • Electrophoretic Mobility Shift Assay
  • Embryo, Mammalian
  • Enhancer Elements, Genetic
  • GA-Binding Protein Transcription Factor
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins
  • In Situ Hybridization
  • Limb Buds
  • Mice
  • Mice, Transgenic
  • Point Mutation
  • Polydactyly
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins c-ets
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • Regulatory Elements, Transcriptional
  • Transcription Factors

Cite this

Lettice, L. A., Williamson, I., Wiltshire, J. H., Peluso, S., Devenney, P. S., Hill, A. E., Essafi, A., Hagman, J., Mort, R., Grimes, G., DeAngelis, C. L., & Hill, R. E. (2012). Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Developmental Cell, 22(2), 459-467. https://doi.org/10.1016/j.devcel.2011.12.010