title: Smad7 modulates TGFβ signaling during cranial suture development to maintain suture patency.
abstract: Craniosynostosis, the premature fusion of one or more sutures between the calvarial bones, is a common birth defect. Mutations in genes encoding receptors for the transforming growth factor-beta (TGFβ) family of signaling molecules have been associated with craniosynostosis, but how TGFβ signaling is regulated during suture development is not known. In the present study, we found that expression of Smad2 and Smad3, intracellular mediators of canonical TGFβ signaling, gradually increases during early postnatal suture development in rat in both the coronal suture (CS), which remains patent throughout life, and the posterior frontal suture (PFS), which undergoes programmed closure by postnatal day 22. The amounts of phosphorylated Smad2 and Smad3 proteins showed a similar gradual increase in the PFS and CS, but in the CS, Smad2/3 activation was suppressed after neonatal day 10. The suppression of Smad2/3 activation in the CS correlated with upregulation of Smad7 expression. We demonstrate that siRNA-mediated knockdown of Smad7 caused increased phosphorylation of Smad2 and Smad3 and induced osseous obliteration of the CS from postnatal days 10 to 22. The Smad7 siRNA-induced CS closure was associated with significantly increased levels of Fgf10 and phosphorylated ERK1/2 in the suture mesenchyme. Moreover, addition of the Erk1/2 inhibitor U0126 partially blocked Smad7-siRNA-induced CS closure. These findings suggest that canonical TGFβ signaling induces suture closure at least in part through activation of FGF and ERK signaling and that Smad7 plays an important role in maintaining suture patency by suppressing canonical TGFβ signaling during suture development.
authors: State Key Laboratory of Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral and Maxillofacial Surgery, Sichuan Provincial People's Hospital, Sichuan Provincial Academy of Medical Science, Chengdu, China.
authors: Hao
authors: H
authors: Zhou
authors: Shujuan
authors: S
authors: Zou
authors: Yu
authors: Y
authors: Lan
authors: Wei
authors: W
authors: Fei
authors: Rulang
authors: R
authors: Jiang
authors: Jing
authors: J
authors: Hu
mesh_terms: D000818:Animals; D001483:Base Sequence; D003393:Cranial Sutures / Q000378:metabolism / Q000502:physiology*; D017931:DNA Primers; D055785:Gene Knockdown Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D016212:Transforming Growth Factor beta
keywords: CRANIAL SUTURE; CRANIOSYNOSTOSIS; FUSION; PATENCY; SMAD7; TGFβ