Document Detail


Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice.
MedLine Citation:
PMID:  23281127     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Yoshihiro Komatsu; Paul B Yu; Nobuhiro Kamiya; Haichun Pan; Tomokazu Fukuda; Gregory J Scott; Manas K Ray; Ken-Ichi Yamamura; Yuji Mishina
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  28     ISSN:  1523-4681     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-22     Completed Date:  2013-12-09     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1422-33     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Society for Bone and Mineral Research.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Morphogenetic Protein Receptors, Type I / antagonists & inhibitors,  genetics,  metabolism
Bone Morphogenetic Proteins / genetics,  metabolism*
Craniosynostoses / embryology*,  genetics,  metabolism,  pathology
Humans
Mice
Mice, Transgenic
Mutation
Neural Crest / embryology*,  metabolism,  pathology
Pyrazoles / pharmacology
Pyrimidines / pharmacology
Signal Transduction*
Smad Proteins / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
ES071003-11/ES/NIEHS NIH HHS; K08 HL079943/HL/NHLBI NIH HHS; K08HL079943/HL/NHLBI NIH HHS; K99DE021054/DE/NIDCR NIH HHS; R01 AR057374/AR/NIAMS NIH HHS; R01 DE020843/DE/NIDCR NIH HHS; R01AR057374/AR/NIAMS NIH HHS; R01DE020843/DE/NIDCR NIH HHS; Z01 ES071003-11/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Bone Morphogenetic Proteins; 0/LDN 193189; 0/Pyrazoles; 0/Pyrimidines; 0/Smad Proteins; EC 2.7.11.30/BMPR1A protein, human; EC 2.7.11.30/Bmpr1a protein, mouse; EC 2.7.11.30/Bone Morphogenetic Protein Receptors, Type I
Comments/Corrections

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