Cellular Endocrinology Lab, National Institute of Immunology, New Delhi, India.
Reproductive Physiology Lab, Department of Zoology, University of Delhi, New Delhi, India.
Andrology. 2021 Mar;9(2):689-699. doi: 10.1111/andr.12941. Epub 2020 Nov 23.
Infertility has become a global phenomenon and constantly declining sperm count in males in modern world pose a major threat to procreation of humans. Male fertility is critically dependent on proper functioning of testicular Sertoli cells. Defective Sertoli cell proliferation and/or impaired functional maturation may be one of the underlying causes of idiopathic male infertility. Using high-throughput "omics" approach, we found binding sites for homeobox transcription factor MEIS1 on the promoters of several genes up-regulated in pubertal (mature) Sertoli cells, indicating that MEIS1 may be crucial for Sertoli cell-mediated regulation of spermatogenesis at and after puberty.
To decipher the role of transcription factor MEIS1 in Sertoli cell maturation and spermatogenesis.
Sc-specific Meis1 knockdown (KD) transgenic mice were generated using pronuclear microinjection. Morphometric and histological analysis of the testes from transgenic mice was performed to identify defects in spermatogenesis. Epididymal sperm count and litter size were analyzed to determine the effect of Meis1 knockdown on fertility.
Sertoli cell (Sc)-specific Meis1 KD led to massive germ cell loss due to apoptosis and impaired spermatogenesis. Unlike normal pubertal Sc, the levels of SOX9 in pubertal Sc of Meis1 KD were significantly high, like immature Sc. A significant reduction in epididymal sperm count was observed in these mice. The mice were found to be infertile or sub-fertile (with reduced litter size), depending on the extent of Meis1 inhibition.
The results of this study demonstrated for the first time, a role of Meis1 in Sc maturation and normal spermatogenic progression. Inhibition of Meis1 in Sc was associated with deregulated spermatogenesis and a consequent decline in fertility of the transgenic mice.
Our results provided substantial evidence that suboptimal Meis1 expression in Sc may be one of the underlying causes of idiopathic infertility.
不孕不育已成为全球性现象，而现代男性精子数量不断下降，对人类生育构成了重大威胁。男性生育能力取决于睾丸支持细胞的正常功能。支持细胞增殖缺陷和/或功能成熟受损可能是特发性男性不育的潜在原因之一。我们采用高通量“组学”方法，发现同源盒转录因子 MEIS1 在青春期（成熟）支持细胞中上调的几个基因启动子上具有结合位点，这表明 MEIS1 可能对青春期后支持细胞介导的精子发生调控至关重要。
解析转录因子 MEIS1 在支持细胞成熟和精子发生中的作用。
使用原核显微注射法生成 Sc 特异性 Meis1 敲低（KD）转基因小鼠。对转基因小鼠的睾丸进行形态计量学和组织学分析，以鉴定精子发生缺陷。分析附睾精子计数和产仔数，以确定 Meis1 敲低对生育能力的影响。
Sc 特异性 Meis1 KD 导致大量生殖细胞凋亡和精子发生受损而丢失。与正常青春期 Sc 不同，Meis1 KD 青春期 Sc 中的 SOX9 水平明显升高，类似于未成熟 Sc。这些小鼠的附睾精子计数显著减少。这些小鼠表现为不育或亚不育（产仔数减少），具体取决于 Meis1 抑制的程度。
这项研究的结果首次证明了 Meis1 在支持细胞成熟和正常精子发生进展中的作用。Meis1 在 Sc 中的抑制与精子发生失调和转基因小鼠生育力下降有关。
我们的研究结果提供了充分的证据表明，Sc 中 Meis1 表达不足可能是特发性不育的潜在原因之一。
