The targeting and functions of miRNA-383 are mediated by FMRP during spermatogenesis.
The targeting and functions of miRNA-383 are mediated by FMRP during spermatogenesis.
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精子发生过程中 miRNA-383 的靶向和功能由 FMRP 介导
DOI：
10.1038/cddis.2013.138
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发表时间：
2013-05-02
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
我们以前的研究表明，microRNA-383（miR-383）表达下调，在不育男性成熟停滞（MA）的睾丸。睾丸miR-383表达异常可能加强男性不育与睾丸生殖细胞肿瘤之间的联系。然而，miR-383在精子发生过程中的靶向和功能机制仍然未知。在本研究中，我们发现脆性X智力低下蛋白（FMRP）与小鼠睾丸中包括miR-383在内的88个miRNAs相关。在NTERA-2（NT 2）（睾丸胚胎癌）细胞中敲低FMRP通过降低FMRP与miR-383之间的相互作用增强miR-383诱导的细胞增殖抑制，然后影响miR-383与其靶基因3′-非翻译区的结合，包括干扰素调节因子1（IRF 1）和细胞周期蛋白D1（Cyclin D1）在体内和体外。另一方面，在NT 2细胞和GC 1（精原细胞生殖细胞系）中过表达miR-383也下调FMRP水平。miR-383直接靶向Cyclin D1，抑制其下游效应子磷酸化pRb和E2 F1，最终导致FMRP表达降低。在Fmr 1敲除小鼠和FMRP下调的MA患者的睾丸中也观察到miR-383表达减少、细胞周期蛋白依赖性激酶4表达失调（miR-383的下游基因之一）和DNA损伤增加。FMRP和miR-383在精子发生过程中可能存在反馈环，FMRP是miR-383功能的负调节因子。我们的数据还表明，FMRP-miR-383通路的失调可能部分导致MA的人类生精障碍。
Our previous studies have shown that microRNA-383 (miR-383) expression is downregulated in the testes of infertile men with maturation arrest (MA). Abnormal testicular miR-383 expression may potentiate the connections between male infertility and testicular germ cell tumors. However, the mechanisms underlying the targeting and functions of miR-383 during spermatogenesis remain unknown. In this study, we found that fragile X mental retardation protein (FMRP) was associated with 88 miRNAs in mouse testis including miR-383. Knockdown of FMRP in NTERA-2 (NT2)(testicular embryonal carcinoma) cells enhanced miR-383-induced suppression of cell proliferation by decreasing the interaction between FMRP and miR-383, and then affecting miR-383 binding to the 3′-untranslated region of its target genes, including interferon regulatory factor-1 (IRF1) and Cyclin D1 both in vivo and in vitro. On the other hand, FMRP levels were also downregulated by overexpression of miR-383 in NT2 cells and GC1 (spermatogonia germ cell line). miR-383 targeted to Cyclin D1 directly, and then inhibited its downstream effectors, including phosphorylated pRb and E2F1, which ultimately resulted in decreased FMRP expression. Reduced miR-383 expression, dysregulated cyclin-dependent kinase 4 expression (one of the downstream genes of miR-383) and increased DNA damage were also observed in the testes of Fmr1 knockout mice and of MA patients with a downregulation of FMRP. A potential feedback loop between FMRP and miR-383 during spermatogenesis is proposed, and FMRP acts as a negative regulator of miR-383 functions. Our data also indicate that dysregulation of the FMRP–miR-383 pathway may partially contribute to human spermatogenic failure with MA.
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影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
16
作者：
Lal A;Navarro F;Maher CA;Maliszewski LE;Yan N;O'Day E;Chowdhury D;Dykxhoorn DM;Tsai P;Hofmann O;Becker KG;Gorospe M;Hide W;Lieberman J
通讯作者：
Lieberman J
影响因子：
10.5
作者：
Caudy, AA;Myers, M;Hammond, SM
通讯作者：
Hammond, SM
影响因子：
10.5
作者：
Fernandez, PC;Frank, SR;Amati, B
通讯作者：
Amati, B
影响因子：
4.8
作者：
Fasanaro, Pasquale;D'Alessandra, Yuri;Martelli, Fabio
通讯作者：
Martelli, Fabio