Cellular Endocrinology Laboratory, National Institute of Immunology, New Delhi, India.
Department of Zoology, Hemvati Nandan Bahuguna Garhwal University, Srinagar, Uttarakhand, India.
Mol Hum Reprod. 2020 Oct 1;26(10):760-772. doi: 10.1093/molehr/gaaa055.
The alarming decline in sperm count has become a global concern in the recent decades. The division and differentiation of male germ cells (Gc) into sperm are governed by Sertoli cells (Sc) upon their functional maturation during puberty. However, the roles of genes regulating pubertal maturation of Sc have not been fully determined. We have observed that Tetraspanin 8 (Tspan8) is down-regulated in Sc during puberty in rats. However, there has been no in vivo evidence for a causal link between the down-regulation of Tspan8 expression and the onset of spermatogenesis as yet. To investigate this, we generated a novel transgenic (Tg) rat, in which the natural down-regulation of Tspan8 was prevented specifically in Sc from puberty up to adulthood. Adult Tg male rats showed around 98% reduction in sperm count despite having a similar level of serum testosterone (T) as the controls. Functional maturation of Sc was impaired as indicated by elevated levels of Amh and low levels of Kitlg and Claudin11 transcripts. The integrity of the blood testis barrier was compromised due to poor expression of Gja1 and Gc apoptosis was discernible. This effect was due to a significant rise in both Mmp7 and phospho P38 MAPK in Tg rat testis. Taken together, we demonstrated that the natural down-regulation of Tspan8 in Sc during puberty is a prerequisite for establishing male fertility. This study divulges one of the aetiologies of certain forms of idiopathic male infertility where somatic cell defect, but not hormonal deficiency, is responsible for impaired spermatogenesis.
在最近几十年，精子数量的惊人下降已成为全球关注的问题。在青春期，精子细胞（Gc）的分裂和分化受到支持细胞（Sc）的调控。然而，调控 Sc 青春期成熟的基因的作用尚未完全确定。我们观察到，在青春期大鼠的 Sc 中，四跨膜蛋白 8（Tspan8）的表达下调。然而，迄今为止，还没有体内证据表明 Tspan8 表达下调与精子发生的开始之间存在因果关系。为了研究这一点，我们生成了一种新型转基因（Tg）大鼠，其中 Tspan8 的自然下调在青春期到成年期期间在 Sc 中被特异性阻止。成年 Tg 雄性大鼠的精子计数减少了约 98%，尽管它们的血清睾酮（T）水平与对照组相似。Sc 的功能成熟受损，表现为 Amh 水平升高，Kitlg 和 Claudin11 转录物水平降低。由于 Gja1 的表达不佳和 Gc 凋亡可辨，血睾屏障的完整性受到损害。这种效应是由于 Tg 大鼠睾丸中 Mmp7 和磷酸化 P38 MAPK 的显著增加所致。总之，我们证明了青春期 Sc 中 Tspan8 的自然下调是建立男性生育能力的前提。这项研究揭示了某些特发性男性不育症的病因之一，其中体细胞缺陷而不是激素缺乏导致精子发生受损。
