Cranial base synostosis in mice caused by upregulation of Wnt following partial inhibition of Shh.

IF 4.5 1区 生物学 Q1 BIOLOGY
Jiangping Chen, Chengyan Ren, Chuanqing Mao, Yongzhen Lai, Meng Lu, Yuanjing Jiang, Weihui Chen
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引用次数: 0

Abstract

Background: The cranial base develops from multipotent mesenchymal cells through endochondral ossification. Genetic ablation of Sonic hedgehog (Shh) or Smoothened (Smo) leads to early apoptosis of cranial base cells, thus limiting the study of their role in the early development of cranial base. Our previous studies have shown that administration of 150 mg/kg Vismodegib (a Smo-specific small molecule antagonist) in E9.5- or E10.5-mice leads to premature mineralization of the skull base synchondroses. In the current study, we further investigated the molecular mechanisms underlying this model.

Results: Mice exposed to Vismodegib exhibit premature hypertrophic differentiation and osteogenesis of the cranial base synchondroses after E14.5. However, the expression of Patched1 (Ptch1), Gli1, parathyroid hormone-related protein (PTHrP), and Phh3 was not downregulated in exposure mice. We demonstrate that Shh and Wnt signaling pathways were activated in the cranial base region at E10.5. Administration of Vismodegib at E10.5 transiently inhibited Shh signaling in the cranial base area and caused upregulation of β-catenin expression along with ectopic expression of lymphoid enhancer-binding factor 1 (Lef1) and Runx2 in the ventral mesenchymal cells of the cranial base primordium at E12.5. Diverse degrees of cranial base craniosynostosis induced by various doses of Vismodegib suggest a dose-dependent effect of Shh in early basicranium development.

Conclusions: The present experiment suggests that early activation of Shh standardizes normal embryonic development of cranial base after initial morphogenesis, which may be mediated through the "antagonistic" effect of Shh signaling on Wnt signaling. Our study provides new insights into the role of signal-crosstalk in early morphogenesis of the cranial base.

Shh部分抑制后Wnt上调引起的小鼠颅底关节闭锁。
背景:颅基底是由多能间充质细胞通过软骨内成骨形成的。基因消融Sonic hedgehog (Shh)或Smoothened (Smo)可导致颅基底细胞早期凋亡,从而限制了其在颅基底早期发育中的作用的研究。我们之前的研究表明,在E9.5或e10.5小鼠中施用150 mg/kg Vismodegib(一种smo特异性小分子拮抗剂)会导致颅底联合软骨过早矿化。在目前的研究中,我们进一步研究了该模型的分子机制。结果:暴露于Vismodegib的小鼠在E14.5后表现出过早的肥厚分化和颅底联合软骨成骨。然而,在暴露小鼠中,Patched1 (Ptch1)、Gli1、甲状旁腺激素相关蛋白(PTHrP)和Phh3的表达并未下调。我们证明Shh和Wnt信号通路在E10.5时在颅底区被激活。在E10.5时给予Vismodegib可瞬时抑制颅基底区Shh信号,并引起E12.5时颅基底原基腹侧间充质细胞β-catenin表达上调,同时淋巴细胞增强因子结合因子1 (Lef1)和Runx2异位表达。不同剂量Vismodegib诱导的不同程度颅底颅缝闭合提示Shh在早期颅底发育中的剂量依赖性作用。结论:本实验提示,Shh的早期激活规范了颅基底在初始形态发生后的正常胚胎发育,这可能是通过Shh信号对Wnt信号的“拮抗”作用介导的。我们的研究为信号串扰在颅底早期形态发生中的作用提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Biology
BMC Biology 生物-生物学
CiteScore
7.80
自引率
1.90%
发文量
260
审稿时长
3 months
期刊介绍: BMC Biology is a broad scope journal covering all areas of biology. Our content includes research articles, new methods and tools. BMC Biology also publishes reviews, Q&A, and commentaries.
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