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The BMP antagonist noggin regulates cranial suture fusion

Abstract

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.

References

  1. Slavkin, H. C. Developmental Craniofacial Biology (Lea & Febiger, Philadelphia, 1979)

    Google Scholar 

  2. Thilander, B. Basic mechanisms in craniofacial growth. Acta Odontol. Scand. 53, 144–151 (1995)

    Article  CAS  Google Scholar 

  3. McCarthy, J. G., Epstein, F. J. & Wood-Smith, D. in Plastic Surgery (ed. McCarthy, J. G.) 3013–3053 (W.B. Saunders Co., Philadelphia, 1990)

    Google Scholar 

  4. Cohen, M. M. Jr Craniosynostoses: phenotypic/molecular correlations. Am. J. Med. Genet. 56, 334–339 (1995)

    Article  Google Scholar 

  5. Wilkie, A. O. M. Craniosynostosis: genes and mechanisms. Hum. Mol. Genet. 6, 1647–1656 (1997)

    Article  CAS  Google Scholar 

  6. Brunet, L. J., McMahon, J. A., McMahon, A. P. & Harland, R. M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280, 1455–1457 (1998)

    Article  ADS  CAS  Google Scholar 

  7. McMahon, J. A. et al. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 12, 1438–1452 (1998)

    Article  CAS  Google Scholar 

  8. Capdevila, J. & Johnson, R. L. Endogenous and ectopic expression of noggin suggests a conserved mechanism for regulation of BMP function during limb and somite patterning. Dev. Biol. 197, 205–217 (1998)

    Article  CAS  Google Scholar 

  9. Warren, S. M. et al. New developments in cranial suture research. Plast. Reconstr. Surg. 107, 523–540 (2001)

    Article  CAS  Google Scholar 

  10. Opperman, L. A., Nolen, A. A. & Ogle, R. C. TGF-beta 1, TGF-beta 2, and TGF-beta 3 exhibit distinct patterns of expression during cranial suture formation and obliteration in vivo and in vitro. J. Bone Miner. Res. 12, 301–310 (1997)

    Article  CAS  Google Scholar 

  11. Greenwald, J. A. et al. Regional differentiation of cranial suture-associated dura mater in vivo and in vitro: implications for suture fusion and patency. J. Bone Miner. Res. 15, 2413–2430 (2000)

    Article  CAS  Google Scholar 

  12. Wozney, J. M. et al. Novel regulators of bone formation: Molecular clones and activities. Science 242, 1528–1534 (1988)

    Article  ADS  CAS  Google Scholar 

  13. Wang, E. A. et al. Recombinant human bone morphogenetic protein induces bone formation. Proc. Natl Acad. Sci. USA 87, 2220–2224 (1990)

    Article  ADS  CAS  Google Scholar 

  14. Zimmerman, L. B., De Jesus-Escobar, J. M. & Harland, R. M. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86, 599–606 (1996)

    Article  CAS  Google Scholar 

  15. Hsu, D. R., Economides, A. N., Wang, X., Eimon, P. M. & Harland, R. M. The Xenopus dorsalizing factor gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol. Cell 1, 673–683 (1998)

    Article  CAS  Google Scholar 

  16. Capdevila, J., Tsukui, T., Rodriquez Esteban, C., Zappavigna, V. & Izpisua Belmonte, J. C. Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by gremlin. Mol. Cell 4, 839–849 (1999)

    Article  CAS  Google Scholar 

  17. Minabe-Saegusa, C., Saegusa, H., Tsukahara, M. & Noguchi, S. Sequence and expression of a novel mouse gene PRDC (protein related to DAN and cerberus) identified by a gene trap approach. Dev. Growth Differ. 40, 343–353 (1998)

    Article  CAS  Google Scholar 

  18. Brunkow, M. E. et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet. 68, 577–589 (2001)

    Article  CAS  Google Scholar 

  19. Gazzerro, E., Gangji, V. & Canalis, E. Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts. J. Clin. Invest. 102, 2106–2114 (1998)

    Article  CAS  Google Scholar 

  20. Greenwald, J. A. et al. In vivo modulation of FGF biological activity alters cranial suture fate. Am. J. Pathol. 158, 441–452 (2001)

    Article  CAS  Google Scholar 

  21. Moore, R., Ferretti, P., Copp, A. & Thorogood, P. Blocking endogenous FGF-2 activity prevents cranial osteogenesis. Dev. Biol. 243, 99–114 (2002)

    Article  CAS  Google Scholar 

  22. Mansukhani, A., Bellosta, P., Sahni, M. & Basilico, C. Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J. Cell Biol. 149, 1297–1308 (2000)

    Article  CAS  Google Scholar 

  23. Bradley, J. P. et al. Studies in cranial suture biology: in vitro cranial suture fusion. Cleft Palate–Craniofac. J. 33, 150–156 (1996)

    Article  CAS  Google Scholar 

  24. Dixon, M. E., Armstrong, P., Stevens, D. B. & Bamshad, M. Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalagism. Gen. Med. 3, 349–353 (2001)

    CAS  Google Scholar 

  25. Roth, D. A. et al. Studies in cranial suture biology. I. Increased immunoreactivity for transforming growth factor-beta (β1, β2, β3) during rat cranial suture fusion. J. Bone Miner. Res. 12, 311–321 (1997)

    Article  CAS  Google Scholar 

  26. Bradley, J. P., Levine, J. P., Roth, D. A., McCarthy, J. G. & Longaker, M. T. Studies in cranial suture biology. IV. Temporal sequence of posterior frontal cranial suture fusion in the mouse. Plast. Reconstr. Surg. 98, 1039–1045 (1996)

    Article  CAS  Google Scholar 

  27. Albrecht, U., Helms, J. A. & Lin, H. in Molecular and Cellular Methods in Developmental Toxicology (ed. Daston, G. P.) 23–48 (CRC Press, Boca Raton, 1997)

    Google Scholar 

  28. Paine-Saunders, S., Viviano, B. L., Economides, A. N. & Saunders, S. Heparan sulfate proteoglycans retain noggin at the cell surface: A potential mechanism for shaping bone morphogenetic protein gradients. J. Biol. Chem. 277, 2089–2096 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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). https://doi.org/10.1038/nature01545

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