title: The targeting and functions of miRNA-383 are mediated by FMRP during spermatogenesis.
abstract: 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.
authors: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
authors: H
authors: H
authors: Tian
authors: Y-X
authors: YX
authors: Cao
authors: X-S
authors: XS
authors: Zhang
authors: W-P
authors: WP
authors: Liao
authors: Y-H
authors: YH
authors: Yi
authors: J
authors: J
authors: Lian
authors: L
authors: L
authors: Liu
authors: H-L
authors: HL
authors: Huang
authors: W-J
authors: WJ
authors: Liu
authors: M-M
authors: MM
authors: Yin
authors: M
authors: M
authors: Liang
authors: G
authors: G
authors: Shan
authors: F
authors: F
authors: Sun
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D013737:Testis / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D050687:E2F1 Transcription Factor; D051860:Fragile X Messenger Ribonucleoprotein 1; D050856:Interferon Regulatory Factor-1; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C577009:MIRN383 microRNA, mouse
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