Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis.
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.
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Stephen R F
SR
Twigg
Elena
E
Vorgia
Simon J
SJ
McGowan
Ioanna
I
Peraki
Aimée L
AL
Fenwick
Vikram P
VP
Sharma
Maryline
M
Allegra
Andreas
A
Zaragkoulias
Elham
E
Sadighi Akha
Samantha J L
SJ
Knight
Helen
H
Lord
Tracy
T
Lester
Louise
L
Izatt
Anne K
AK
Lampe
Shehla N
SN
Mohammed
Fiona J
FJ
Stewart
Alain
A
Verloes
Louise C
LC
Wilson
Chris
C
Healy
Paul T
PT
Sharpe
Peter
P
Hammond
Jim
J
Hughes
Stephen
S
Taylor
David
D
Johnson
Steven A
SA
Wall
George
G
Mavrothalassitis
Andrew O M
AO
Wilkie
D000818:Animals; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism; D003393:Cranial Sutures / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D003398:Craniosynostoses / Q000235:genetics / Q000503:physiopathology; D047108:Embryonic Development / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010012:Osteogenesis / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
D050657:Core Binding Factor alpha Subunits; C107465:ERF protein, human; C522019:Erf protein, mouse; D012097:Repressor Proteins; D018808:Transcription Factor AP-1