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

Authors

  • Yoshihiro Komatsu,

    1. Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
    2. Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
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  • Paul B Yu,

    1. Division of Cardiology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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  • Nobuhiro Kamiya,

    1. Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
    2. Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
    3. Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX, USA
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  • Haichun Pan,

    1. Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
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  • Tomokazu Fukuda,

    1. Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
    2. Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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  • Gregory J Scott,

    1. Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
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  • Manas K Ray,

    1. Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
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  • Ken-ichi Yamamura,

    1. Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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  • Yuji Mishina PhD

    Corresponding author
    1. Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
    2. Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
    • Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
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Address correspondence to: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, 1011 North University Avenue, Ann Arbor, MI 48109, USA. E-mail: mishina@umich.edu

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.

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