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Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 Loci

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  • Stefano Comazzetto
  • Monica Di Giacomo
  • Kasper Dindler Rasmussen
  • Christian Much
  • Chiara Azzi
  • Emerald Perlas
  • Marcos Morgan
  • Donal O'Carroll

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Original languageEnglish
Article number1004597
Number of pages11
JournalPLoS Genetics
Volume10
Issue number10
DOIs
Publication statusPublished - 16 Oct 2014

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.

    Research areas

  • male germ-cells, miRNA biogenesis, micro biogenesis, RNA-interference, gene expression, Messenger RNA, mouse oocytes, dicer, Spermatogenesis, requires

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