The BMP antagonist noggin regulates cranial suture fusion

Warren, Stephen M.
Brunet, Lisa J.
Harland, Richard M.
Economides, Aris N.
Longaker, Michael T.

* Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5148, USA
† Department of Molecular and Cell Biology, Division of Biochemistry and Molecular Biology, University of California, Berkeley, California 94720-3204, USA
‡ Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591-6707, USA

Received 2 October 2002; accepted 7 March 2003; doi:10.1038/nature01545.

Supplementary Information accompanies the paper on Nature's website (➧ www.nature.com/nature).

Correspondence and requests for materials should be addressed to M.T.L.

Nature 422(6932):p 625-629, April 10, 2003.

During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors (fgfr) are associated with syndromic forms of craniosynostosis. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning. Here we show thatnogginis expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and thatnogginexpression is suppressed by FGF2 and syndromicfgfrsignalling. Sincenogginmisexpression prevents cranial suture fusionin vitroandin vivo,we suggest that syndromicfgfr-mediated craniosynostoses may be the result of inappropriate downregulation ofnogginexpression.