Opposing Functions of the ETS Factor Family Define Shh Spatial Expression in Limb Buds and Underlie Polydactyly
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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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Functional analysis of the ZRS enhancer revealed that these mutations either create gain-of-function binding sites for activating transcription factors ETS1 and GABPα, or abolish a repressive transcription factor site, leading to ectopic SHH expression.
“Functional analysis of the ZRS enhancer revealed that these mutations either create gain-of-function binding sites for activating TFs (ETS1 and GABPα) [199], or abolish a repressive TF site [200], leading to ectopic SHH expression.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [199]
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References 37 · Cited by 153
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- Ahn S. Joyner A.L. Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning Cell 118 2004 505 516 15315762
- Farooq M. Troelsen J.T. Boyd M. Eiberg H. Hansen L. Hussain M.S. Rehman S. Azhar A. Ali A. Bakhtiar S.M. Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS Eur. J. Hum. Genet. 18 2010 733 736 20068592 PMC2987342
- Fisher R.J. Koizumi S. Kondoh A. Mariano J.M. Mavrothalassitis G. Bhat N.K. Papas T.S. Human ETS1 oncoprotein. Purification, isoforms, -SH modification, and DNA sequence-specific binding J. Biol. Chem. 267 1992 17957 17965 1517230
- Furniss D. Lettice L.A. Taylor I.B. Critchley P.S. Giele H. Hill R.E. Wilkie A.O. A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb Hum. Mol. Genet. 17 2008 2417 2423 18463159 PMC2486440
- Gurnett C.A. Bowcock A.M. Dietz F.R. Morcuende J.A. Murray J.C. Dobbs M.B. Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly Am. J. Med. Genet. A. 143 2007 27 32 17152067
- Harfe B.D. Scherz P.J. Nissim S. Tian H. McMahon A.P. Tabin C.J. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities Cell 118 2004 517 528 15315763
- Hecksher-Sørensen J. Hill R.E. Lettice L. Double labeling for whole-mount in situ hybridization in mouse Biotechniques 24 1998 914 916 918 9631179
- Hill R.E. How to make a zone of polarizing activity: insights into limb development via the abnormality preaxial polydactyly Dev. Growth Differ. 49 2007 439 448 17661738
- Lettice L.A. Horikoshi T. Heaney S.J. van Baren M.J. van der Linde H.C. Breedveld G.J. Joosse M. Akarsu N. Oostra B.A. Endo N. Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly Proc. Natl. Acad. Sci. USA 99 2002 7548 7553 12032320 PMC124279
- Lettice L.A. Hill A.E. Devenney P.S. Hill R.E. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly Hum. Mol. Genet. 17 2008 978 985 18156157
- Lifanov A.P. Makeev V.J. Nazina A.G. Papatsenko D.A. Homotypic regulatory clusters in Drosophila Genome Res. 13 2003 579 588 12670999 PMC430164
- Maier H. Colbert J. Fitzsimmons D. Clark D.R. Hagman J. Activation of the early B-cell-specific mb-1 (Ig-alpha) gene by Pax-5 is dependent on an unmethylated Ets binding site Mol. Cell. Biol. 23 2003 1946 1960 12612069 PMC149480
- Mao J. McGlinn E. Huang P. Tabin C.J. McMahon A.P. Fgf-dependent Etv4/5 activity is required for posterior restriction of Sonic Hedgehog and promoting outgrowth of the vertebrate limb Dev. Cell 16 2009 600 606 19386268 PMC3164484
- Richardson L. Venkataraman S. Stevenson P. Yang Y. Burton N. Rao J. Fisher M. Baldock R.A. Davidson D.R. Christiansen J.H. EMAGE mouse embryo spatial gene expression database: 2010 update Nucleic Acids Res. 38 Database issue 2010 D703 D709 19767607 PMC2808994
- Ristevski S. Tam P.P. Hertzog P.J. Kola I. Ets2 is expressed during morphogenesis of the somite and limb in the mouse embryo Mech. Dev. 116 2002 165 168 12128217
- Ristevski S. O'Leary D.A. Thornell A.P. Owen M.J. Kola I. Hertzog P.J. The ETS transcription factor GABPalpha is essential for early embryogenesis Mol. Cell. Biol. 24 2004 5844 5849 15199140 PMC480913
- Sagai T. Hosoya M. Mizushina Y. Tamura M. Shiroishi T. Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb Development 132 2005 797 803 15677727
- Semerci C.N. Demirkan F. Ozdemir M. Biskin E. Akin B. Bagci H. Akarsu N.A. Homozygous feature of isolated triphalangeal thumb-preaxial polydactyly linked to 7q36: no phenotypic difference between homozygotes and heterozygotes Clin. Genet. 76 2009 85 90 19519794
- Stock J.K. Giadrossi S. Casanova M. Brookes E. Vidal M. Koseki H. Brockdorff N. Fisher A.G. Pombo A. Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells Nat. Cell Biol. 9 2007 1428 1435 18037880
- Tickle C. Making digit patterns in the vertebrate limb Nat. Rev. Mol. Cell Biol. 7 2006 45 53 16493412
- Towers M. Tickle C. Growing models of vertebrate limb development Development 136 2009 179 190 19103802
- Towers M. Mahood R. Yin Y. Tickle C. Integration of growth and specification in chick wing digit-patterning Nature 452 2008 882 886 18354396
- Tusher V.G. Tibshirani R. Chu G. Significance analysis of microarrays applied to the ionizing radiation response Proc. Natl. Acad. Sci. USA 98 2001 5116 5121 11309499 PMC33173
- Wagner A. Genes regulated cooperatively by one or more transcription factors and their identification in whole eukaryotic genomes Bioinformatics 15 1999 776 784 10705431
- Wieczorek D. Pawlik B. Li Y. Akarsu N.A. Caliebe A. May K.J. Schweiger B. Vargas F.R. Balci S. Gillessen-Kaesbach G. Wollnik B. A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb Hum. Mutat. 31 2010 81 89 19847792
- Xin J.H. Cowie A. Lachance P. Hassell J.A. Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells Genes Dev. 6 1992 481 496 1547944
- Yang Y. Drossopoulou G. Chuang P.T. Duprez D. Marti E. Bumcrot D. Vargesson N. Clarke J. Niswander L. McMahon A. Tickle C. Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb Development 124 1997 4393 4404 9334287
- Zhang Z. Verheyden J.M. Hassell J.A. Sun X. FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds Dev. Cell 16 2009 607 613 19386269 PMC3541528
- Zhu J. Nakamura E. Nguyen M.T. Bao X. Akiyama H. Mackem S. Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud Dev. Cell 14 2008 624 632 18410737 PMC8284562
- Authors
- 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.
- Affiliations
- Western General Hospital (GB)
- National Jewish Health (US)
- Corresponding author
- Hill, Robert E.
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 22
- Issue
- 2
- Pages
- 459-467
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC3314984
- OpenAlex
- W2132117628
- Cited by
- 153
- References
- 37
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 12 · 2023: 9 · 2022: 16 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 13 · 2016: 17 · 2015: 11 · 2014: 17 · 2013: 11 · 2012: 9
- FWCI
- 6.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- National Institutes of Health
- Medical Research Council
- National Institute of Allergy and Infectious Diseases (R01AI081878, R01AI054661)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Sonic hedgehog, ETS transcription factors, zone of polarizing activity, limb bud development, preaxial polydactyly, transcription factor binding sites, digit patterning
- MeSH terms
- Animals, DNA-Binding Proteins, Embryo, Mammalian, Enhancer Elements, Genetic, Mice, Transgenic, RNA, Messenger, Transcription Factors, Blotting, Western, Point Mutation, In Situ Hybridization, Polydactyly, Gene Expression Regulation, Developmental, Limb Buds, Electrophoretic Mobility Shift Assay, Chromatin Immunoprecipitation, Regulatory Elements, Transcriptional, Proto-Oncogene Proteins c-ets, Proto-Oncogene Protein c-ets-1, GA-Binding Protein Transcription Factor, Mice, Hedgehog Proteins, Real-Time Polymerase Chain Reaction
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