The identification of new genes involved in sexual development and gonadal function as potential candidates causing male infertility is important for both diagnostic and therapeutic purposes. Deficiency of the onco-miRNA cluster miR-17∼92 has been shown to disrupt spermatogenesis, whereas mutations in its paralog cluster, miR-106b∼25, that is expressed in the same cells, were reported to have no effect on testis development and function. The aim of this work is to determine the role of these two miRNA clusters in spermatogenesis and male fertility. For this, we analyzed miR-106b∼25 and miR-17∼92 single and double mouse mutants and compared them to control mice. We found that miR-106b∼25 knock out testes show reduced size, oligozoospermia and altered spermatogenesis. Transcriptomic analysis showed that multiple molecular pathways are deregulated in these mutant testes. Nevertheless, mutant males conserved normal fertility even when early spermatogenesis and other functions were disrupted. In contrast, miR-17∼92^+/−; miR-106b∼25^−/− double mutants showed severely disrupted testicular histology and significantly reduced fertility. Our results indicate that miR-106b∼25 and miR-17∼92 ensure accurate gene expression levels in the adult testis, keeping them within the required thresholds. They play a crucial role in testis homeostasis and are required to maintain male fertility. Hence, we have identified new candidate genetic factors to be screened in the molecular diagnosis of human males with reproductive disorders. Finally, considering the well-known oncogenic nature of these two clusters and the fact that patients with reduced fertility are more prone to testicular cancer, our results might also help to elucidate the molecular mechanisms linking both pathologies.

中文翻译：

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onco-miRNA 簇 miR-106b∼25 的缺陷会导致少精子症，并且需要 miR-106b∼25 和 miR-17∼92 的协同作用来维持男性生育能力。

鉴定涉及性发育和性腺功能的新基因作为导致男性不育的潜在候选基因对于诊断和治疗目的都很重要。onco -miRNA 簇miR-17∼92 的缺陷已被证明会破坏精子发生，而其旁系同源簇miR-106b∼25 中的突变据报道在相同的细胞中表达对睾丸发育没有影响，功能。这项工作的目的是确定这两个 miRNA 簇在精子发生和男性生育能力中的作用。为此，我们分析了miR-106b∼25和miR-17∼92单小鼠和双小鼠突变体，并将它们与对照小鼠进行了比较。我们发现miR-106b∼25敲除睾丸显示体积缩小、少精子症和精子发生改变。转录组学分析表明，在这些突变睾丸中，多个分子途径失调。尽管如此，即使早期精子发生和其他功能被破坏，突变雄性仍能保持正常的生育能力。相比之下，miR-17∼92 ^+/-；miR-106b∼25 ^-/-双突变体表现出严重破坏的睾丸组织学和显着降低的生育能力。我们的结果表明miR-106b∼25和miR-17∼92确保成人睾丸中准确的基因表达水平，使它们保持在所需的阈值内。它们在睾丸稳态中起着至关重要的作用，并且是维持男性生育能力所必需的。因此，我们已经确定了新的候选遗传因素，以便在患有生殖障碍的人类男性的分子诊断中进行筛选。最后，考虑到这两个集群众所周知的致癌性质以及生育能力降低的患者更容易患睾丸癌的事实，我们的结果也可能有助于阐明将这两种病理联系起来的分子机制。