Deletion of Transglutaminase 2 from Mouse Astrocytes Significantly Improves Their Ability to Promote Neurite Outgrowth on an Inhibitory Matrix.
Deletion of Transglutaminase 2 from Mouse Astrocytes Significantly Improves Their Ability to Promote Neurite Outgrowth on an Inhibitory Matrix.
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DOI：
10.3390/ijms24076058
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发表时间：
2023-03-23
影响因子：
5.6
通讯作者：
Johnson, Gail V. W.
中科院分区：
文献类型：
--
作者：
Emerson, Jacen;Delgado, Thomas;Girardi, Peter;Johnson, Gail V. W.
星形胶质细胞是中枢神经系统（CNS）的主要支持细胞，有助于维持神经元的能量需求和稳态环境。中枢神经系统损伤导致星形胶质细胞呈现反应性表型，整体功能发生改变，对神经元的恢复可能有支持作用，也可能有害。反应性星形胶质细胞群体的表征是一个快速发展的领域，而控制星形胶质细胞呈现哪种类型的反应性表型的潜在因素和信号通路知之甚少。我们之前的研究表明，转谷氨酰胺酶 2 (TG2) 在确定星形胶质细胞对损伤的反应中具有重要作用。从星形胶质细胞中选择性删除 TG2 可改善中枢神经系统损伤后的功能结果，并引起基因调控的广泛变化，这与其核定位有关。为了开始了解 TG2 如何影响星形胶质细胞功能，我们使用神经元-星形胶质细胞共培养范例来比较 TG2−/− 和野生型 (WT) 小鼠星形胶质细胞对神经突生长和突触形成的影响。神经元在对照基质或由抑制性硫酸软骨素蛋白聚糖（CSPG）组成的损伤模拟基质上生长。与 WT 星形胶质细胞相比，TG2−/− 星形胶质细胞仅在 CSPG 基质上显着更大程度地支持神经突生长，而突触形成测定显示出混合结果，具体取决于所分析的突触前和突触后标记。我们假设 TG2 通过与转录因子和转录复合物相互作用来调节基因表达，从而调节损伤条件下星形胶质细胞的支持功能。基于之前酵母双杂交筛选 TG2 相互作用子的结果，我们进一步研究了 TG2 与 Zbtb7a（一种普遍表达的转录因子）的相互作用。免疫共沉淀和共定位分析证实了 TG2 和 Zbtb7a 在星形胶质细胞核中的相互作用。 WT 和 TG2−/− 星形胶质细胞中 Zbtb7a 水平的过表达或敲低表明，Zbtb7a 强烈影响星形胶质细胞的形态和星形胶质细胞支持神经元生长的能力，而这受到 TG2 存在的显着调节。这些发现支持我们的假设，即星形胶质细胞 TG2 作为转录调节因子影响星形胶质细胞功能，在损伤条件下影响更大，从而增加其表达，并且 Zbtb7a 可能有助于星形胶质细胞 TG2 缺失观察到的总体效果。
Astrocytes are the primary support cells of the central nervous system (CNS) that help maintain the energetic requirements and homeostatic environment of neurons. CNS injury causes astrocytes to take on reactive phenotypes with an altered overall function that can range from supportive to harmful for recovering neurons. The characterization of reactive astrocyte populations is a rapidly developing field, and the underlying factors and signaling pathways governing which type of reactive phenotype that astrocytes take on are poorly understood. Our previous studies suggest that transglutaminase 2 (TG2) has an important role in determining the astrocytic response to injury. Selectively deleting TG2 from astrocytes improves functional outcomes after CNS injury and causes widespread changes in gene regulation, which is associated with its nuclear localization. To begin to understand how TG2 impacts astrocytic function, we used a neuron-astrocyte co-culture paradigm to compare the effects of TG2−/− and wild-type (WT) mouse astrocytes on neurite outgrowth and synapse formation. Neurons were grown on a control substrate or an injury-simulating matrix comprised of inhibitory chondroitin sulfate proteoglycans (CSPGs). Compared to WT astrocytes, TG2−/− astrocytes supported neurite outgrowth to a significantly greater extent only on the CSPG matrix, while synapse formation assays showed mixed results depending on the pre- and post-synaptic markers analyzed. We hypothesize that TG2 regulates the supportive functions of astrocytes in injury conditions by modulating gene expression through interactions with transcription factors and transcription complexes. Based on the results of a previous yeast two-hybrid screen for TG2 interactors, we further investigated the interaction of TG2 with Zbtb7a, a ubiquitously expressed transcription factor. Co-immunoprecipitation and colocalization analyses confirmed the interaction of TG2 and Zbtb7a in the nucleus of astrocytes. Overexpression or knockdown of Zbtb7a levels in WT and TG2−/− astrocytes revealed that Zbtb7a robustly influenced astrocytic morphology and the ability of astrocytes to support neuronal outgrowth, which was significantly modulated by the presence of TG2. These findings support our hypothesis that astrocytic TG2 acts as a transcriptional regulator to influence astrocytic function, with greater influence under injury conditions that increase its expression, and Zbtb7a likely contributes to the overall effects observed with astrocytic TG2 deletion.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1016/j.bbamcr.2011.09.012
发表时间：
2012-02
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Gundemir S;Colak G;Tucholski J;Johnson GV
通讯作者：
Johnson GV
影响因子：
4.8
作者：
Filiano, Anthony J.;Bailey, Craig D. C.;Johnson, Gail V. W.
通讯作者：
Johnson, Gail V. W.
影响因子：
64.8
作者：
Davies, SJA;Fitch, MT;Silver, J
通讯作者：
Silver, J
影响因子：
7.2
作者：
Chung WS;Allen NJ;Eroglu C
通讯作者：
Eroglu C