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The BMP antagonist noggin regulates cranial suture fusion


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 plates1. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex2. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation3. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors (fgfr) are associated with syndromic forms of craniosynostosis4,5. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning6,7,8. Here we show that noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since noggin misexpression prevents cranial suture fusion in vitro and in vivo, we suggest that syndromic fgfr-mediated craniosynostoses may be the result of inappropriate downregulation of noggin expression.

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Figure 1: BMP4 and noggin expression in patent and fusing sutures.
Figure 2: BMP4-induced Noggin expression in primary osteoblasts and dural cells is suppressed by FGF2 and fgfr2 gain-of-function mutations.
Figure 3: FGF2 suppresses noggin expression in coronal dura mater in vivo.
Figure 4: Noggin misexpression maintains posterior frontal suture patency in vivo.

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We thank C. J. Tabin, I. Thesleff, D. M. Kingsley and N. Quarto for comments and suggestions on this manuscript, and K. D. Fong, J. A. Mathy and R. P. Nacamuli for their technical assistance. The human fgfr2, fgfr2/S252W (Apert) and fgfr2/C342Y (Crouzon) retroviral constructs were provided by A. Mansukhami and C. Basilico (New York University). This work was supported by NIH grants (R.M.H. and M.T.L.) and a Lyndon Peer/PSEF Fellowship (S.M.W.).

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Correspondence to Michael T. Longaker.

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Warren, S., Brunet, L., Harland, R. et al. The BMP antagonist noggin regulates cranial suture fusion. Nature 422, 625–629 (2003).

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