Children's Surgical Research Program, Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Dev Biol. 2010 Aug 15;344(2):922-40. doi: 10.1016/j.ydbio.2010.06.009. Epub 2010 Jun 12.
Premature closure of cranial sutures, which serve as growth centers for the skull vault, result in craniosynostosis. In the mouse posterior frontal (PF) suture closes by endochondral ossification, whereas sagittal (SAG) remain patent life time, although both are neural crest tissue derived. We therefore, investigated why cranial sutures of same tissue origin adopt a different fate. We demonstrated that closure of the PF suture is tightly regulated by canonical Wnt signaling, whereas patency of the SAG suture is achieved by constantly activated canonical Wnt signaling. Importantly, the fate of PF and SAG sutures can be reversed by manipulating Wnt signaling. Continuous activation of canonical Wnt signaling in the PF suture inhibits endochondral ossification and therefore, suture closure, In contrast, inhibition of canonical Wnt signaling in the SAG suture, upon treatment with Wnt antagonists results in endochondral ossification and suture closure. Thus, inhibition of canonical Wnt signaling in the SAG suture phenocopies craniosynostosis. Moreover, mice haploinsufficient for Twist1, a target gene of canonical Wnt signaling which inhibits chondrogenesis, have sagittal craniosynostosis. We propose that regulation of canonical Wnt signaling is of crucial importance during the physiological patterning of PF and SAG sutures. Importantly, dysregulation of this pathway may lead to craniosynostosis.
颅缝过早闭合会导致颅缝早闭，颅缝是颅盖骨的生长中心。在小鼠中，额骨后缝（PF）通过软骨内骨化闭合，而矢状缝（SAG）则终生保持开放，尽管它们都来源于神经嵴组织。因此，我们研究了为什么来自同一组织的颅缝会有不同的命运。我们证明，PF 缝的闭合受到经典 Wnt 信号的严格调控，而 SAG 缝的开放则是通过持续激活的经典 Wnt 信号实现的。重要的是，通过操纵 Wnt 信号可以逆转 PF 和 SAG 缝的命运。在 PF 缝中持续激活经典 Wnt 信号会抑制软骨内骨化，从而导致缝闭合。相反，在 SAG 缝中抑制经典 Wnt 信号，通过使用 Wnt 拮抗剂处理，会导致软骨内骨化和缝闭合。因此，在 SAG 缝中抑制经典 Wnt 信号会模拟颅缝早闭。此外，Twist1 基因杂合缺失的小鼠，即经典 Wnt 信号的靶基因，可抑制软骨生成，会出现矢状颅缝早闭。我们提出，经典 Wnt 信号的调节在 PF 和 SAG 缝的生理模式形成过程中至关重要。重要的是，该途径的失调可能导致颅缝早闭。
