title: Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice.
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.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kamiya
authors.forename: Haichun
authors.initials: H
authors.lastname: Pan
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Fukuda
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Scott
authors.forename: Manas K
authors.initials: MK
authors.lastname: Ray
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D003398:Craniosynostoses / Q000196:embryology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; C554430:LDN 193189; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; C498211:BMPR1A protein, human; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I