Journal
NATURE GENETICS
Volume 45, Issue 3, Pages 308-313Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2539
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Funding
- Greek Ministry of Education [PYTHAGORAS II KA2092, PENED 03ED626, HERAKLEITOS II KA 3396, SYNERGASIA 09SYN-11-902]
- NIHR Biomedical Research Centre
- Department of Health's NIHR Biomedical Research Centres funding scheme
- Oxford Craniofacial Unit Charitable Fund
- Department of Health, UK, Quality, Improvement, Development and Initiative Scheme (QIDIS) (YES)
- Wellcome Trust [090532, 093329]
- Medical Research Council [G0901599, MR/J006742/1] Funding Source: researchfish
- MRC [G0901599] Funding Source: UKRI
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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(1). Here, we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs. 2-7), 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 similar 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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