학술논문
Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis.
Document Type
Article
Author
Twigg, Stephen R F; Vorgia, Elena; McGowan, Simon J; Peraki, Ioanna; Fenwick, Aimée L; Sharma, Vikram P; Allegra, Maryline; Zaragkoulias, Andreas; Akha, Elham Sadighi; Knight, Samantha J L; Lord, Helen; Lester, Tracy; Izatt, Louise; Lampe, Anne K; Mohammed, Shehla N; Stewart, Fiona J; Verloes, Alain; Wilson, Louise C; Healy, Chris; Sharpe, Paul T
Source
Subject
*CRANIOSYNOSTOSES
*MITOGEN-activated protein kinases
*PHOSPHORYLATION
*BONE growth
*PROTEIN kinases
*ANIMAL models in research
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Language
ISSN
1061-4036
Abstract
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. [ABSTRACT FROM AUTHOR]