mTORC1 Signaling is a Critical Regulator of Postnatal Tendon Development.
mTORC1 Signaling is a Critical Regulator of Postnatal Tendon Development.
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DOI：
10.1038/s41598-017-17384-0
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发表时间：
2017-12-07
影响因子：
4.6
通讯作者：
Joeng KS
中科院分区：
文献类型：
--
作者：
Lim J;Munivez E;Jiang MM;Song IW;Gannon F;Keene DR;Schweitzer R;Lee BH;Joeng KS
肌腱在肌肉骨骼组织之间传递收缩力。尽管肌腱的生物力学特性已被广泛研究，但调控出生后肌腱发育的分子机制尚不清楚。在这里，我们使用小鼠遗传方法研究mTORC1信号在出生后肌腱发育中的作用。移除肌腱中的Raptor导致mTORC1信号丢失，导致出生后严重的肌腱缺陷，包括肌腱厚度减少，这表明mTORC1是出生后肌腱发育所必需的。相反，肌腱中mTORC1信号的激活增加了肌腱细胞的数量和增殖。此外，Tsc1条件敲除小鼠在肌腱中间物质中出现严重的胶原纤维紊乱和新生血管。有趣的是，在Raptor和Tsc1条件敲除小鼠中，胶原纤维直径显著减少，尽管严重程度有所不同。我们使用跟腱进行RNA-seq分析，以研究这些跟腱表型背后的分子变化。Raptor条件敲除小鼠显示细胞外基质（ECM）结构相关基因表达降低，而Tsc1条件敲除小鼠显示调节TGF-β/BMP/FGF信号的基因以及控制ECM结构和拆卸的基因发生变化。总的来说，我们的研究表明，维持mTORC1信号的生理水平对于出生后肌腱的发育和成熟至关重要。
Tendons transmit contractile forces between musculoskeletal tissues. Whereas the biomechanical properties of tendons have been studied extensively, the molecular mechanisms regulating postnatal tendon development are not well understood. Here we examine the role of mTORC1 signaling in postnatal tendon development using mouse genetic approaches. Loss of mTORC1 signaling by removal of Raptor in tendons caused severe tendon defects postnatally, including decreased tendon thickness, indicating that mTORC1 is necessary for postnatal tendon development. By contrast, activation of mTORC1 signaling in tendons increased tendon cell numbers and proliferation. In addition, Tsc1 conditional knockout mice presented severely disorganized collagen fibers and neovascularization in the tendon midsubstance. Interestingly, collagen fibril diameter was significantly reduced in both Raptor and Tsc1 conditional knockout mice, albeit with variations in severity. We performed RNA-seq analysis using Achilles tendons to investigate the molecular changes underlying these tendon phenotypes. Raptor conditional knockout mice showed decreased extracellular matrix (ECM) structure-related gene expression, whereas Tsc1 conditional knockout mice exhibited changes in genes regulating TGF-β/BMP/FGF signaling, as well as in genes controlling ECM structure and disassembly. Collectively, our studies suggest that maintaining physiological levels of mTORC1 signaling is essential for postnatal tendon development and maturation.
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影响因子：
2.3
作者：
Jelinsky SA;Rodeo SA;Li J;Gulotta LV;Archambault JM;Seeherman HJ
通讯作者：
Seeherman HJ
影响因子：
4.6
作者：
Schwartz, Andrea G.;Long, Fanxin;Thomopoulos, Stavros
通讯作者：
Thomopoulos, Stavros
影响因子：
4.6
作者：
Pryce, Brian A.;Watson, Spencer S.;Schweitzer, Ronen
通讯作者：
Schweitzer, Ronen
影响因子：
4.6
作者：
Murchison, Nicholas D.;Price, Brian A.;Schweitzer, Ronen
通讯作者：
Schweitzer, Ronen
影响因子：
2.8
作者：
Davies, Michael R.;Ravishankar, Bharat;Feeley, Brian T.
通讯作者：
Feeley, Brian T.