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: 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
• Journal: Developmental cell (Dev Cell) Vol. 22 Issue 2 Pg. 459-67 (Feb 14 2012) ISSN: 1878-1551 [Electronic] United States
• PMID: 22340503 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• Ets1 protein, mouse
• Etv4 protein, mouse
• Etv5 protein, mouse
• GA-Binding Protein Transcription Factor
• Gabpa protein, mouse
• Hedgehog Proteins
• Proto-Oncogene Protein c-ets-1
• Proto-Oncogene Proteins c-ets
• RNA, Messenger
• Shh protein, mouse
• Transcription Factors

Topics

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