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.

Chronic low-dose exposure to a mixture of environmental endocrine disruptors induces microRNAs/isomiRs deregulation in mouse concomitant with intratesticular estradiol reduction

“…miR-34b-5p is involved in the regulation of genes relevant for cell cycle control, apoptosis, and infertility 23, 24 . Thus, it could explain the increased cell death observed in the testes of mice exposed to the EDCs mixture.…”

Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit

“…Hence, increased expression of these cell-cycle proteins in TKO mice represents a direct effect of their derepression upon miR-34/ 449 ablation. miRNAs of the miR-34/449 family were also reported to be involved in spermatogenesis (21,36,37). In particular, miR-34b/c and miR-449a/b/c are required for proper execution of meiosis in male gametes and during the maturation of spermatids (36).…”

“…miRNAs of the miR-34/449 family were also reported to be involved in spermatogenesis (21,36,37). In particular, miR-34b/c and miR-449a/b/c are required for proper execution of meiosis in male gametes and during the maturation of spermatids (36). It is likely that both the involvement of this miRNA family in spermatogenesis as well as their role in multicilia formation in the efferent ducts of the testes, described in our study, contribute to the infertility observed in male TKO mice.…”

The role of epigenetics in idiopathic male infertility

“…Interestingly, miR-34c has also been shown to promote murine male germ cell apoptosis by targeting the transcription factor ATF1 in a p53-independent manner [122]. In mouse models, miR-34c and miR-34b were found to be highly expressed in post-mitotic male germ cells from primary spermatocytes up to round spermatids [121,123], and deletion of this locus along with miR-449 led to OAT and infertility [124]. Remarkably, miR-34c seems to extend its reproductive role into the zygote, as sperm-borne miR-34c has been shown to Patients with oligoospermia / oligoasthenozoospermia (80) and NOA (40) Spermatozoa and testicular tissues miR-429 was significantly increased, whereas miR-34b*, miR-34b, miR-34c-5p…”