ERVWE1 Reduces Hippocampal Neuron Density and Impairs Dendritic Spine Morphology through Inhibiting Wnt/JNK Non-Canonical Pathway via miR-141-3p in Schizophrenia.
ERVWE1 Reduces Hippocampal Neuron Density and Impairs Dendritic Spine Morphology through Inhibiting Wnt/JNK Non-Canonical Pathway via miR-141-3p in Schizophrenia.
复制标题
DOI：
10.3390/v15010168
复制
发表时间：
2023-01-05
期刊：
影响因子：
--
通讯作者：
Zhu F
中科院分区：
文献类型：
--
作者：
Yao W;Zhou P;Yan Q;Wu X;Xia Y;Li W;Li X;Zhu F
人类内源性逆转录病毒（HERV）是外源性逆转录病毒感染祖先生殖系的残余物。人内源性逆转录病毒W家族包膜基因（HERV-W env，也称ERVWE 1）位于染色体7 q21 -22，编码HERV-W家族的包膜糖蛋白。越来越多的证据表明，ERVWE 1的异常表达涉及精神分裂症的病因。此外，遗传学和形态学研究表明，树突棘缺陷可能有助于精神分裂症的发病。我们报道ERVWE 1通过miR-141- 3 p抑制Wingless-type（Wnt）/c-Jun N-末端激酶（JNK）非经典通路，改变精神分裂症患者树突棘的密度和形态。在本文中，我们发现miR-141- 3 p水平升高，并与ERVWE 1显著正相关的精神分裂症。此外，精神分裂症患者血清Wnt 5a和肌动蛋白相关蛋白2（Arp 2）水平降低，并与ERVWE 1呈显著负相关。体外实验发现ERVWE 1通过与转录因子Yin Yang 1（YY 1）相互作用上调miR-141- 3 p的表达。YY 1通过与miR-141- 3 p的启动子结合来调节miR-141- 3 p的表达。荧光素酶检测结果显示，YY 1能增强miR-141- 3 p的启动子活性。利用miRNA靶点预测数据库和荧光素酶报告基因分析，我们证明miR-141- 3 p靶向Wnt 5a的3'非翻译区（3' UTR）。ERVWE 1通过非经典途径Wnt 5a/JNK信号通路抑制Arp 2的表达。此外，ERVWE 1还通过miR-141- 3 p抑制Wnt 5a/JNK/Arp 2信号通路。最后，功能检测显示ERVWE 1通过miR-141- 3 p抑制Wnt/JNK非经典通路，诱导精神分裂症海马神经元形态和棘密度异常。我们的研究结果表明，miR-141- 3 p，Wnt 5a和Arp 2可能是精神分裂症的潜在临床血液生物标志物或治疗靶点。我们的工作也为ERVWE 1在精神分裂症发病机制中的作用提供了新的见解。
Human endogenous retroviruses (HERVs) are remnants of ancestral germline infections by exogenous retroviruses. Human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1), located on chromosome 7q21-22, encodes an envelope glycoprotein from the HERV-W family. Mounting evidence suggests that aberrant expression of ERVWE1 involves the etiology of schizophrenia. Moreover, the genetic and morphological studies indicate that dendritic spine deficits may contribute to the onset of schizophrenia. Here, we reported that ERVWE1 changed the density and morphology of the dendritic spine through inhibiting Wingless-type (Wnt)/c-Jun N-terminal kinases (JNK) non-canonical pathway via miR-141-3p in schizophrenia. In this paper, we found elevated levels of miR-141-3p and a significant positive correlation with ERVWE1 in schizophrenia. Moreover, serum Wnt5a and actin-related protein 2 (Arp2) levels decreased and demonstrated a significant negative correlation with ERVWE1 in schizophrenia. In vitro experiments disclosed that ERVWE1 up-regulated miR-141-3p expression by interacting with transcription factor (TF) Yin Yang 1 (YY1). YY1 modulated miR-141-3p expression by binding to its promoter. The luciferase assay revealed that YY1 enhanced the promoter activity of miR-141-3p. Using the miRNA target prediction databases and luciferase reporter assays, we demonstrated that miR-141-3p targeted Wnt5a at its 3’ untranslated region (3′ UTR). Furthermore, ERVWE1 suppressed the expression of Arp2 through non-canonical pathway, Wnt5a/JNK signaling pathway. In addition, ERVWE1 inhibited Wnt5a/JNK/Arp2 signal pathway through miR-141-3p. Finally, functional assays showed that ERVWE1 induced the abnormalities in hippocampal neuron morphology and spine density through inhibiting Wnt/JNK non-canonical pathway via miR-141-3p in schizophrenia. Our findings indicated that miR-141-3p, Wnt5a, and Arp2 might be potential clinical blood-based biomarkers or therapeutic targets for schizophrenia. Our work also provided new insight into the role of ERVWE1 in schizophrenia pathogenesis.
登录
查看更多内容
影响因子：
11
作者：
Chen, C.;Cheng, L.;Grennan, K.;Pibiri, F.;Zhang, C.;Badner, J. A.;Gershon, E. S.;Liu, C.
通讯作者：
Liu, C.
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
影响因子：
14.8
作者：
Beaudoin, Gerard M. J., III;Lee, Seung-Hye;Arikkath, Jyothi
通讯作者：
Arikkath, Jyothi
HERV-W env 通过激活 TRPC3 通道并抑制人神经母细胞瘤细胞中的 DISC1 来调节钙内流
影响因子：
3.2
作者：
Chen, Yatang;Yan, Qiujin;Zhu, Fan
通讯作者：
Zhu, Fan
影响因子：
16
作者：
Cory, GOC;Cramer, R;Ridley, AJ
通讯作者：
Ridley, AJ