| Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. | |
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MedLine Citation:
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PMID: 23354439 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The extracellular signal-related kinases 1 and 2 (ERK1/2) are key proteins mediating mitogen-activated protein kinase signaling downstream of RAS: phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple targets. Here, we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf levels reduced to ∼30% of normal exhibit postnatal multiple-suture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to elements away from promoters that contain RUNX or AP-1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes. |
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Authors:
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Stephen R F Twigg; Elena Vorgia; Simon J McGowan; Ioanna Peraki; Aimée L Fenwick; Vikram P Sharma; Maryline Allegra; Andreas Zaragkoulias; Elham Sadighi Akha; Samantha J L Knight; Helen Lord; Tracy Lester; Louise Izatt; Anne K Lampe; Shehla N Mohammed; Fiona J Stewart; Alain Verloes; Louise C Wilson; Chris Healy; Paul T Sharpe; Peter Hammond; Jim Hughes; Stephen Taylor; David Johnson; Steven A Wall; George Mavrothalassitis; Andrew O M Wilkie |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-27 |
Journal Detail:
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Title: Nature genetics Volume: - ISSN: 1546-1718 ISO Abbreviation: Nat. Genet. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9216904 Medline TA: Nat Genet Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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