title: Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 loci.
abstract: Male fertility requires the continuous production of high quality motile spermatozoa in abundance. Alterations in all three metrics cause oligoasthenoteratozoospermia, the leading cause of human sub/infertility. Post-mitotic spermatogenesis inclusive of several meiotic stages and spermiogenesis (terminal spermatozoa differentiation) are transcriptionally inert, indicating the potential importance for the post-transcriptional microRNA (miRNA) gene-silencing pathway therein. We found the expression of miRNA generating enzyme Dicer within spermatogenesis peaks in meiosis with critical functions in spermatogenesis. In an expression screen we identified two miRNA loci of the miR-34 family (miR-34b/c and miR-449) that are specifically and highly expressed in post-mitotic male germ cells. A reduction in several miRNAs inclusive of miR-34b/c in spermatozoa has been causally associated with reduced fertility in humans. We found that deletion of both miR34b/c and miR-449 loci resulted in oligoasthenoteratozoospermia in mice. MiR-34bc/449-deficiency impairs both meiosis and the final stages of spermatozoa maturation. Analysis of miR-34bc-/-;449-/- pachytene spermatocytes revealed a small cohort of genes deregulated that were highly enriched for miR-34 family target genes. Our results identify the miR-34 family as the first functionally important miRNAs for spermatogenesis whose deregulation is causal to oligoasthenoteratozoospermia and infertility.
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Comazzetto
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Di Giacomo
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Kasper Dindler
authors.initials: KD
authors.lastname: Rasmussen
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Much
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Azzi
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Emerald
authors.initials: E
authors.lastname: Perlas
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Marcos
authors.initials: M
authors.lastname: Morgan
authors.affiliation: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
authors.forename: Dónal
authors.initials: D
authors.lastname: O'Carroll
mesh_terms: D000818:Animals; D053627:Asthenozoospermia / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics; D005786:Gene Expression Regulation; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008938:Mitosis; D009845:Oligospermia / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000502:physiology
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C538721:Mirn449 microRNA, mouse; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases