Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice

Yoshihiro Komatsu, Paul B. Yu, Nobuhiro Kamiya, Haichun Pan, Tomokazu Fukuda, Gregory J. Scott, Manas K. Ray, Ken Ichi Yamamura, Yuji Mishina

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1422-1433
Number of pages12
JournalJournal of Bone and Mineral Research
Volume28
Issue number6
DOIs
Publication statusPublished - 2013 Jun

Keywords

  • BMP
  • CRANIOSYNOSTOSIS
  • NEURAL CREST CELLS
  • SMAD-SIGNALING
  • SUTURE

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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