OASIS regulates chondroitin 6-O-sulfotransferase 1 gene transcription in the injured adult mouse cerebral cortex
OASIS regulates chondroitin 6-O-sulfotransferase 1 gene transcription in the injured adult mouse cerebral cortex
复制标题
OASIS 调节受损成年小鼠大脑皮层中软骨素 6-O-磺基转移酶 1 基因的转录
作者：
Okuda H;Tatsumi K;Horii-Hayashi N;Morita S;Okuda-Yamamoto A;Imaizumi K;Wanaka A
老星形胶质细胞特异性诱导物质（OASIS）是cAMP反应元件结合/激活转录因子家族的碱性亮氨酸拉链转录因子，在体内反应性星形胶质细胞中被诱导，在内质网蛋白质合成的质量控制中具有重要作用。反应性星形胶质细胞通过上调硫酸软骨素蛋白聚糖（CSPG）为轴突再生创造一个不允许的环境。在这项研究中，我们重点关注 OASIS 在成年小鼠大脑皮层 CSPG 产生中的潜在作用。与野生型小鼠相比，代表硫酸软骨素部分的 CS-C 免疫反应性在 OASIS 基因敲除小鼠的刺伤皮质中显着减弱。接下来，我们检测了 OASIS 敲除小鼠和野生型小鼠刺伤皮质中 CSPG 合成酶和 CSPG 核心蛋白的表达。野生型小鼠皮质刺伤后，软骨素 6-O-磺基转移酶 1（C6ST1，参与 CSPG 硫酸化的主要酶之一）mRNA 和蛋白质水平升高，但 OASIS 敲除小鼠的皮质刺伤后却没有升高。在大鼠 C6 神经胶质瘤细胞中过表达的 C 末端缺失突变体 OASIS 通过与第一个内含子区域相互作用来增加 C6ST1 转录。在涂有经表皮生长因子处理的星形胶质细胞膜部分的培养皿中，培养的海马神经元的神经突生长受到抑制，所述星形胶质细胞来自野生型，但不来自 OASIS 敲除小鼠。这些结果表明 OASIS 调节 C6ST1 的转录，从而促进星形胶质细胞中的 CSPG 硫酸化。通过这些机制，OASIS 可以调节受损大脑皮层的轴突再生。OASIS 是一种 ER 应激反应性 CREB/ATF 家族成员，在受损大脑的反应性星形胶质细胞中表达上调。我们发现上调的 OASIS 参与 C6ST1 基因的转录调控，促进硫酸软骨素蛋白多糖 (CSPG) 硫酸化。我们得出结论，OASIS 通过建立不允许轴突再生的微环境来发挥抗再生转录因子的作用。
Old astrocyte specifically induced substance (OASIS), a basic leucine zipper transcription factor of the cAMP response element binding/Activating transcription factor family, is induced in reactive astrocytesin vivoand has important roles in quality control of protein synthesis at the endoplasmic reticulum. Reactive astrocytes produce a non‐permissive environment for regenerating axons by up‐regulating chondroitin sulfate proteoglycans (CSPGs). In this study, we focus on the potential role of OASIS in CSPG production in the adult mouse cerebral cortex. CS‐C immunoreactivity, which represents chondroitin sulfate moieties, was significantly attenuated in the stab‐injured cortices of OASIS knockout mice compared to those of wild‐type mice. We next examined expression of the CSPG‐synthesizing enzymes and core proteins of CSPGs in the stab‐injured cortices of OASIS knockout and wild‐type mice. The levels of chondroitin 6‐O‐sulfotransferase 1 (C6ST1, one of the major enzymes involved in sulfation of CSPGs) mRNA and protein increased after cortical stab injury of wild‐type, but not of OASIS knockout, mice. A C‐terminal deletion mutant OASIS over‐expressed in rat C6 glioma cells increased C6ST1 transcription by interacting with the first intron region. Neurite outgrowth of cultured hippocampal neurons was inhibited on culture dishes coated with membrane fractions of epidermal growth factor‐treated astrocytes derived from wild type but not from OASIS knockout mice. These results suggest that OASIS regulates the transcription of C6ST1 and thereby promotes CSPG sulfation in astrocytes. Through these mechanisms, OASIS may modulate axonal regeneration in the injured cerebral cortex.OASIS, an ER stress‐responsive CREB/ATF family member, is up‐regulated in the reactive astrocytes of the injured brain. We found that the up‐regulated OASIS is involved in the transcriptional regulation of C6ST1 gene, which promotes chondroitin sulfate proteoglycan (CSPG) sulfation. We conclude that OASIS functions as an anti‐regenerative transcription factor by establishing a non‐permissive microenvironment to regenerating axons.