RNA Binding Motif 5 Gene Deletion Modulates Cell Signaling in a Sex-Dependent Manner but Not Hippocampal Cell Death
RNA Binding Motif 5 Gene Deletion Modulates Cell Signaling in a Sex-Dependent Manner but Not Hippocampal Cell Death
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DOI：
10.1089/neu.2021.0362
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发表时间：
2022-03-01
影响因子：
4.2
通讯作者：
Jackson, Travis C.
中科院分区：
文献类型：
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作者：
Farooq, Jeffrey;Snyder, Kara;Jackson, Travis C.
RNA结合基序5（RBM 5）是癌细胞中的促死亡肿瘤抑制基因。它是否在大脑中具有神经毒性，或者它在中枢神经系统（CNS）中是否起着根本不同的作用，仍有待确定。给予脑特异性RBM 5敲除（KO）小鼠受控皮质撞击（CCI）创伤性脑损伤（TBI）。急性细胞损伤和修复的标记物在CCI后48小时的海马匀浆中进行测量。CCI后7天评估海马CA 1/CA 3细胞计数，以确定损伤标志物的早期变化是否与组织学结果相关。凋亡标志物（caspase 3、caspase 6和caspase 9）水平无基因型依赖性差异。然而，KO雌性动物的促死亡钙蛋白酶激活标志物（145/150-血影蛋白和分解产物[SBDP]）和DNA修复/存活标志物出现矛盾性增加。（pH2A.x和pCREB）。CCI损伤的雄性科斯的磷酸化钙/钙调蛋白依赖性蛋白激酶II（pCaMKII）显著增加。尽管在参与细胞死亡途径的急性细胞信号传导靶点的水平上科斯存在性别/基因型依赖性差异，但7天海马神经元存活率与野生型（WT）没有差异。同样，未观察到星形胶质细胞增生的差异。最后，基因分析显示，女性KO海马中雌激素受体α（ER α）水平增加，并可能提出一种新的机制来解释性别对细胞信号传导的影响。总之，RBM 5抑制并不影响体内TBI后海马的存活，但确实改变了参与神经信号转导/Ca 2+信号通路的靶点。研究结果支持这样的观点，即RBM 5在CNS中的作用可能与其在癌症中的传统促死亡作用不同。
RNA-binding motif 5 (RBM5) is a pro-death tumor suppressor gene in cancer cells. It remains to be determined if it is neurotoxic in the brain or rather if it plays a fundamentally different role in the central nervous system (CNS). Brain-specific RBM5 knockout (KO) mice were given a controlled cortical impact (CCI) traumatic brain injury (TBI). Markers of acute cellular damage and repair were measured in hippocampal homogenates 48 h post-CCI. Hippocampal CA1/CA3 cell counts were assessed 7 days post-CCI to determine if early changes in injury markers were associated with histological outcome. No genotype-dependent differences were found in the levels of apoptotic markers (caspase 3, caspase 6, and caspase 9). However, KO females had a paradoxical increase in markers of pro-death calpain activation (145/150-spectrin and breakdown products [SBDP]) and in DNA repair/survival markers. (pH2A.x and pCREB). CCI-injured male KOs had a significant increase in phosphorylated calcium/calmodulin-dependent protein kinase II (pCaMKII). Despite sex/genotype-dependent differences in KOs in the levels of acute cell signaling targets involved in cell death pathways, 7 day hippocampal neuronal survival did not differ from that of wild types (WTs). Similarly, no differences in astrogliosis were observed. Finally, gene analysis revealed increased estrogen receptor alpha (ER alpha) levels in the KO hippocampus in females and may suggest a novel mechanism to explain sex-dimorphic effects on cell signaling. In summary, RBM5 inhibition did not affect hippocampal survival after a TBI in vivo but did modify targets involved in neural signal transduction/Ca2+ signaling pathways. Findings here support the view that RBM5 may serve a purpose in the CNS that is dissimilar from its traditional pro-death role in cancer.