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Human Molecular Genetics, 2000, Vol. 9, No. 13 2001-2008
© 2000 Oxford University Press

A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures

Yong-Xing Zhou, Xiaoling Xu, Lin Chen, Cuiling Li, Steven G. Brodie and Chu-Xia Deng+

Genetics of Development and Disease Branch, NIDDK, NIH, 10/9N105, 10 Center Drive, Bethesda, MD 20892, USA

Pfeiffer syndrome is a classic form of craniosynostosis that is caused by a proline->arginine substitution at amino acid 252 (Pro252Arg) in fibroblast growth factor receptor 1 (FGFR1). Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums. Analysis of the posterior and anterior frontal, sagittal and coronal sutures of early post-natal mutant mice revealed premature fusion. The sutures of mutant mice had accelerated osteoblast proliferation and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Of note, dramatically increased expression of core-binding transcription factor {alpha} subunit type 1 (Cbfa1) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro, where we demonstrate that transfection with wild-type or mutant Fgfr1 induces Cbfa1 expression. The induced expression was also observed using Fgf ligands (Fgf2 and Fgf8). These studies provide direct genetic evidence that the Pro252Arg mutation in FGFR1 causes human Pfeiffer syndrome and uncovers a molecular mechanism in which Fgf/Fgfr1 signals regulate intramembraneous bone formation by modulating Cbfa1 expression.

+ To whom correspondence should be addressed. Tel: +1 301 402 7225; Fax: +1 301 480 1135; Email: chuxiad@bdg10.niddk.nih.gov


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