Document Detail


Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis.
MedLine Citation:
PMID:  23354439     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-27
Journal Detail:
Title:  Nature genetics     Volume:  45     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-26     Completed Date:  2013-05-30     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  308-13     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE42936; RefSeq/NC_000019;  NM_006494;  NM_010155; SWISSPROT/P11308;  P14921;  P17947;  P19419;  P32519;  P41212;  P43268;  P50548;  P78545;  Q06546
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MeSH Terms
Descriptor/Qualifier:
Animals
Core Binding Factor alpha Subunits / metabolism
Cranial Sutures / growth & development,  metabolism,  pathology
Craniosynostoses* / genetics,  physiopathology
Embryonic Development / genetics
Fibroblasts / cytology,  metabolism
Humans
MAP Kinase Signaling System*
Mice
Molecular Sequence Data
Mutation
Osteogenesis / genetics*
Repressor Proteins / genetics*
Signal Transduction
Transcription Factor AP-1 / metabolism
Grant Support
ID/Acronym/Agency:
090532//Wellcome Trust; 090532//Wellcome Trust; 093329//Wellcome Trust; 093329//Wellcome Trust; G0901599//Medical Research Council; MR/J006742/1//Medical Research Council; //Department of Health
Chemical
Reg. No./Substance:
0/Core Binding Factor alpha Subunits; 0/ERF protein, human; 0/Erf protein, mouse; 0/Repressor Proteins; 0/Transcription Factor AP-1
Comments/Corrections

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