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

doi:10.1016/j.devcel.2011.12.010

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 journal › Article (Academic Journal) › peer-review

118 Citations (Scopus)

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).

Original language	English
Pages (from-to)	459-467
Number of pages	9
Journal	Developmental Cell
Volume	22
Issue number	2
DOIs	https://doi.org/10.1016/j.devcel.2011.12.010
Publication status	Published - 14 Feb 2012

Bibliographical note

Keywords

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

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10.1016/j.devcel.2011.12.010

http://www.cell.com/developmental-cell/retrieve/pii/S1534580711005764

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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

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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).",

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AU - Hill, Alison E

AU - Essafi, Abdelkader

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N2 - 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).

AB - 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).

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DO - 10.1016/j.devcel.2011.12.010

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SP - 459

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JO - Developmental Cell

JF - Developmental Cell

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

Abstract

Bibliographical note

Keywords

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