Erf levels affect cranial suture cell differentiation.

Haploinsufficiency of the ETS2 repressor factor (ERF) causes late onset craniosynostosis in humans (OMIM 600775; CRS4) and mice, preceded by mildly reduced calvarium ossification, suggesting a multiphasic role of Erf in the development of the disease. Here we provide insights into the effect of ERF levels on calvarial osteogenesis and the amelioration of craniosynostosis. Ex vivo isolation, propagation and characterization of suture-derived mesenchymal stem and progenitor cells indicate that Erf is required for the initial commitment towards the osteogenic lineage, while at a later stage it is essential for the maintenance of proliferating cells undergoing differentiation. Erf insufficiency results in a decreased population of proliferating suture cells, instigating the premature closure of sutures. In vivo administration of two pharmacological inhibitors that increase nuclear Erf levels in mice with craniosynostosis caused by Erf deficiency, supports the hypothesis of the multiphasic role of this factor in calvarial ossification and suggests that Erf activity modulation could provide an effective pharmacological intervention in craniosynostosis.