Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury
Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury
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DOI：
10.1002/glia.22424
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发表时间：
2013-02-01
期刊：
影响因子：
6.2
通讯作者：
Brown, Arthur
中科院分区：
文献类型：
--
作者：
Mckillop, William M.;Dragan, Magdalena;Brown, Arthur
硫酸软骨素蛋白聚糖（CSPG）发现在神经元周围的网络和神经胶质瘢痕脊髓损伤后，已被证明抑制轴突的生长和可塑性。由于我们之前已经确定SOX 9作为一种转录因子，上调与原代星形胶质细胞培养物中胶质瘢痕形成相关的一系列基因的表达，我们预测，条件性Sox 9消融将导致脊髓损伤后CSPG表达减少，这将导致神经可塑性增加和运动恢复改善。使对照和Sox 9条件性敲除小鼠在胸9级经受70 kdyne挫伤脊髓损伤。损伤后一周，与对照组相比，Sox 9条件性基因敲除小鼠在受损脊髓中表达的CSPG生物合成酶（Xt-1和C4 st）、CSPG核心蛋白（短蛋白聚糖、神经蛋白聚糖和聚集蛋白聚糖）、胶原蛋白2a 1和4a 1以及星形胶质细胞活化标志物GFAP水平降低。基因表达的这些变化伴随着后肢功能和运动恢复的改善，如通过Basso小鼠量表（BMS）和啮齿动物活动盒所评估的。组织学评估证实减少CSPG沉积和胶原性瘢痕的Sox 9条件性基因敲除小鼠的病变，并表现出增加的损伤半影区的神经递质阳性纤维和增加的5-羟色胺免疫反应性尾侧的损伤部位。这些结果表明，SOX 9抑制是治疗SCI的潜在策略。(c)2012 Wiley Periodicals，Inc.
Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI. (c) 2012 Wiley Periodicals, Inc.