Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis

Stephen R. F. Twigg, Elena Vorgia, Simon J. McGowan, Ioanna Peraki, Aimee 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 Mohammed , Fiona J. Stewart, Alain Verloes, Louise C. Wilson, Chris Healy, Paul T. SharpePeter Hammond, Jim Hughes, Stephen Taylor, David Johnson, Steven A. Wall, George Mavrothalassitis*, Andrew O. M. Wilkie

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

133 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)308-313
Number of pages6
JournalNature Genetics
Volume45
Issue number3
DOIs
Publication statusPublished - Mar 2013

Keywords

  • TRANSCRIPTIONAL REPRESSOR ERF
  • PROTEIN
  • PROLIFERATION
  • CLEIDOCRANIAL DYSPLASIA
  • MUTATIONS
  • SKULL VAULT
  • CANCER CELLS
  • INHIBITION
  • DIFFERENTIATION
  • MOUSE MODEL

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