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Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice.
J Bone Miner Res 2013; 28(6):1422-33JB

Abstract

Craniosynostosis describes conditions in which one or more sutures of the infant skull are prematurely fused, resulting in facial deformity and delayed brain development. Approximately 20% of human craniosynostoses are thought to result from gene mutations altering growth factor signaling; however, the molecular mechanisms by which these mutations cause craniosynostosis are incompletely characterized, and the causative genes for diverse types of syndromic craniosynostosis have yet to be identified. Here, we show that enhanced bone morphogenetic protein (BMP) signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells, but not in osteoblasts, causes premature suture fusion in mice. In support of a requirement for precisely regulated BMP signaling, this defect was rescued on a Bmpr1a haploinsufficient background, with corresponding normalization of Smad phosphorylation. Moreover, in vivo treatment with LDN-193189, a selective chemical inhibitor of BMP type I receptor kinases, resulted in partial rescue of craniosynostosis. Enhanced signaling of the fibroblast growth factor (FGF) pathway, which has been implicated in craniosynostosis, was observed in both mutant and rescued mice, suggesting that augmentation of FGF signaling is not the sole cause of premature fusion found in this model. The finding that relatively modest augmentation of Smad-dependent BMP signaling leads to premature cranial suture fusion suggests an important contribution of dysregulated BMP signaling to syndromic craniosynostoses and potential strategies for early intervention.

Authors+Show Affiliations

Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23281127

Citation

Komatsu, Yoshihiro, et al. "Augmentation of Smad-dependent BMP Signaling in Neural Crest Cells Causes Craniosynostosis in Mice." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 28, no. 6, 2013, pp. 1422-33.
Komatsu Y, Yu PB, Kamiya N, et al. Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice. J Bone Miner Res. 2013;28(6):1422-33.
Komatsu, Y., Yu, P. B., Kamiya, N., Pan, H., Fukuda, T., Scott, G. J., ... Mishina, Y. (2013). Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 28(6), pp. 1422-33. doi:10.1002/jbmr.1857.
Komatsu Y, et al. Augmentation of Smad-dependent BMP Signaling in Neural Crest Cells Causes Craniosynostosis in Mice. J Bone Miner Res. 2013;28(6):1422-33. PubMed PMID: 23281127.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice. AU - Komatsu,Yoshihiro, AU - Yu,Paul B, AU - Kamiya,Nobuhiro, AU - Pan,Haichun, AU - Fukuda,Tomokazu, AU - Scott,Gregory J, AU - Ray,Manas K, AU - Yamamura,Ken-Ichi, AU - Mishina,Yuji, PY - 2012/07/19/received PY - 2012/11/19/revised PY - 2012/12/05/accepted PY - 2013/1/3/entrez PY - 2013/1/3/pubmed PY - 2013/12/16/medline SP - 1422 EP - 33 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 28 IS - 6 N2 - Craniosynostosis describes conditions in which one or more sutures of the infant skull are prematurely fused, resulting in facial deformity and delayed brain development. Approximately 20% of human craniosynostoses are thought to result from gene mutations altering growth factor signaling; however, the molecular mechanisms by which these mutations cause craniosynostosis are incompletely characterized, and the causative genes for diverse types of syndromic craniosynostosis have yet to be identified. Here, we show that enhanced bone morphogenetic protein (BMP) signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells, but not in osteoblasts, causes premature suture fusion in mice. In support of a requirement for precisely regulated BMP signaling, this defect was rescued on a Bmpr1a haploinsufficient background, with corresponding normalization of Smad phosphorylation. Moreover, in vivo treatment with LDN-193189, a selective chemical inhibitor of BMP type I receptor kinases, resulted in partial rescue of craniosynostosis. Enhanced signaling of the fibroblast growth factor (FGF) pathway, which has been implicated in craniosynostosis, was observed in both mutant and rescued mice, suggesting that augmentation of FGF signaling is not the sole cause of premature fusion found in this model. The finding that relatively modest augmentation of Smad-dependent BMP signaling leads to premature cranial suture fusion suggests an important contribution of dysregulated BMP signaling to syndromic craniosynostoses and potential strategies for early intervention. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/23281127/Augmentation_of_Smad_dependent_BMP_signaling_in_neural_crest_cells_causes_craniosynostosis_in_mice_ L2 - https://doi.org/10.1002/jbmr.1857 DB - PRIME DP - Unbound Medicine ER -