title: MicroRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting E2F transcription factor-retinoblastoma protein (E2F-pRb) pathway.
abstract: MicroRNAs (miRNAs) mainly function as post-transcriptional regulators and are involved in a wide range of physiological and pathophysiological processes such as cell proliferation, differentiation, apoptosis, and tumorigenesis. Mouse testes express a large number of miRNAs. However, the physiological roles of these testicular miRNAs remain largely unknown. Using microarray and quantitative real time PCR assays, we identified that miRNAs of the microRNA-449 (miR-449) cluster were preferentially expressed in the mouse testis, and their levels were drastically up-regulated upon meiotic initiation during testicular development and in adult spermatogenesis. The expression pattern of the miR-449 cluster resembled that of microRNA-34b/c (miR-34b/c) during spermatogenesis. Further analyses identified that cAMP-responsive element modulator τ and SOX5, two transcription factors essential for regulating male germ cell gene expression, acted as the upstream transactivators to stimulate the expression of the miR-449 cluster in mouse testes. Despite its abundant expression in testicular germ cells, miR-449-null male mice developed normally and exhibited normal spermatogenesis and fertility. Our data further demonstrated that miR-449 shared a cohort of target genes that belong to the E2F transcription factor-retinoblastoma protein pathway with the miR-34 family, and levels of miR-34b/c were significantly up-regulated in miR-449-null testes. Taken together, our data suggest that the miR-449 cluster and miR-34b/c function redundantly in the regulation of male germ cell development in murine testes.
authors.affiliation: Department of Histology and Embryology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Bao
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Jingwen
authors.initials: J
authors.lastname: Wu
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhugang
authors.initials: Z
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Xinkai
authors.initials: X
authors.lastname: Cao
authors.forename: Cizhong
authors.initials: C
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D050684:E2F Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013091:Spermatogenesis; D013737:Testis / Q000378:metabolism*
chemical_list: D050684:E2F Transcription Factors; C522425:MIRN34 microRNA, human; C551848:MIRN34a microRNA, mouse; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; C538721:Mirn449 microRNA, mouse; D016160:Retinoblastoma Protein