有大量证据表明,在人类和动物模型中,microRNA-34/449(miR-34/449)家族对正常的睾丸功能以及成功的精子发生起着至关重要的作用。调节精子的成熟和功能。这篇综述和批判性分析旨在总结miR-34/449失调可能导致男性不育的潜在机制。现有数据表明miR-34/449家族成员调节传出的小导管上皮中的纤毛发生。在miR-34/449失调时,传出导管的纤毛发生明显受损,导致精子聚集和凝集以及生精小管液体的吸收缺陷。这些事件又导致流出道的阻塞,从而导致管状流体的积聚,从而导致进入睾丸的高流体静压力。高静水压会逐渐导致睾丸功能障碍以及生精失败,最后导致男性不育。从严重的少弱精子症到无精子症。此外,miR-34/449家族成员作为精子发生的重要调节因子,在控制几种精子发生相关蛋白的表达模式中起重要作用。已证明这些微小RNA是减数分裂特异性微小RNA,因为它们的表达在精子发生期间的减数分裂起始时相对较高。此外,数据表明,这些分子对于精子本身的正常形成和正常功能至关重要。MicroRNA-34/449家族似乎发挥了显着的抗氧化和抗凋亡特性,因此有助于睾丸稳态调节。考虑到这些微小RNA的临床意义,数据表明miR-34/449家族成员表达的改变与男性不育的几个方面密切相关.最重要的是,精子中miR-34/449的水平,在睾丸组织以及精浆中似乎与男性不育的严重程度直接相关,表明这些microRNAs可以作为潜在的敏感生物标志物,用于准确的个体化鉴别诊断,以及评估男性因素不育症的严重程度。总之,miR-34/449家族的失调会对男性生殖潜能产生不利影响,损害睾丸功能以及精子发生。需要进一步的研究来验证这些结论。
There is a great body of evidence suggesting that in both humans and animal models the microRNA-34/449 (miR-34/449) family plays a crucial role for normal testicular functionality as well as for successful spermatogenesis, regulating spermatozoa maturation and functionality. This
review and critical analysis aims to summarize the potential mechanisms via which miR-34/449 dysregulation could lead to male infertility. Existing data indicate that miR-34/449 family members regulate
ciliogenesis in the efferent ductules epithelium. Upon miR-34/449 dysregulation,
ciliogenesis in the efferent ductules is significantly impaired, leading to sperm aggregation and agglutination as well as to defective reabsorption of the seminiferous tubular fluids. These events in turn cause obstruction of the efferent ductules and thus accumulation of the tubular fluids resulting to high hydrostatic pressure into the testis. High hydrostatic pressure progressively leads to testicular dysfunction as well as to spermatogenic failure and finally to male infertility, which could range from severe oligoasthenozoospermia to azoospermia. In addition, miR-34/449 family members act as significant regulators of spermatogenesis with an essential role in controlling expression patterns of several spermatogenesis-related proteins. It is demonstrated that these microRNAs are meiotic specific microRNAs as their expression is relatively higher at the initiation of meiotic divisions during spermatogenesis. Moreover, data indicate that these molecules are essential for proper formation as well as for proper function of spermatozoa per se. MicroRNA-34/449 family seems to exert significant anti-oxidant and anti-apoptotic properties and thus contribute to testicular homeostatic regulation. Considering the clinical significance of these microRNAs, data indicate that the altered expression of the miR-34/449 family members is strongly associated with several aspects of male infertility. Most importantly, miR-34/449 levels in spermatozoa, in testicular tissues as well as in seminal plasma seem to be directly associated with severity of male infertility, indicating that these microRNAs could serve as potential sensitive biomarkers for an accurate individualized differential diagnosis, as well as for the assessment of the severity of male factor infertility. In conclusion, dysregulation of miR-34/449 family detrimentally affects male reproductive potential, impairing both testicular functionality as well as spermatogenesis. Future studies are needed to verify these conclusions.