Smad proteins differentially regulate transforming growth factor-β-mediated induction of chondroitin sulfate proteoglycans.
Smad proteins differentially regulate transforming growth factor-β-mediated induction of chondroitin sulfate proteoglycans.
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DOI：
10.1111/j.1471-4159.2011.07470.x
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发表时间：
2011-11
影响因子：
4.7
通讯作者：
Symes AJ
中科院分区：
文献类型：
--
作者：
Susarla BT;Laing ED;Yu P;Katagiri Y;Geller HM;Symes AJ
中枢神经系统的创伤性损伤导致硫酸软骨素蛋白聚糖（CSPGs）的表达和沉积增加，抑制轴突再生。转化生长因子-β (TGF-β)被认为是这些变化的主要中介，但TGF-β调节CSPG表达的机制尚不清楚。利用慢病毒表达的Smad特异性shRNA，我们发现TGF-β诱导星形细胞中CSPG的表达依赖于Smad。然而，我们发现合成机制对Smad2和/或Smad3有不同的依赖性。TGF-β诱导神经聚糖和木质素转移酶1需要Smad2和Smad3，而诱导磷酸腺苷和软骨素合成酶1需要Smad2而不需要Smad3。Smad3敲低选择性地减少了星形胶质细胞诱导的4-硫酸转氨酶1和4-硫酸CSPGs的分泌量。此外，Smad3敲低星形胶质细胞更有效地促进TGF-β处理的星形胶质细胞培养的神经元的神经突生长。我们的数据表明TGF -β-Smad3介导的4-硫酸化是星形胶质细胞分泌CSPGs对轴突生长的许可性的关键决定因素。
Traumatic injury to the central nervous system results in increased expression and deposition of chondroitin sulfate proteoglycans (CSPGs) that are inhibitory to axonal regeneration. Transforming growth factor– β (TGF-β) has been implicated as a major mediator of these changes, but the mechanisms through which TGF-β regulates CSPG expression are not known. Using lentiviral expressed Smad-specific shRNA we show that TGF-β induction of CSPG expression in astrocytes is Smad dependent. However, we find a differential dependence of the synthetic machinery on Smad2 and/or Smad3. TGF-β induction of neurocan and xylosyl transferase 1 required both Smad2 and Smad3, whereas induction of phosphacan and chondroitin synthase 1 required Smad2 but not Smad3. Smad3 knockdown selectively reduced induction of chondroitin-4-sulfotransferase 1 and the amount of 4-sulfated CSPGs secreted by astrocytes. Additionally, Smad3 knockdown in astrocytes was more efficacious in promoting neurite outgrowth of neurons cultured on the TGF-β treated astrocytes. Our data implicate TGF–β-Smad3 mediated induction of 4-sulfation as a critical determinant of the permissiveness of astrocyte secreted CSPGs for axonal growth.
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影响因子：
4.3
作者：
Ito, Y;Hikino, M;Sugahara, K
通讯作者：
Sugahara, K
影响因子：
4.8
作者：
Kitagawa, H;Izumikawa, T;Sugahara, K
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影响因子：
8
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Kretschmer, A;Moepert, K;Klippel, A
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Klippel, A
影响因子：
3.4
作者：
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Berry, M
影响因子：
3.5
作者：
Lagord, C;Berry, M;Logan, A
通讯作者：
Logan, A