Globozoospermia is a rare form of male infertility where men produce round-headed sperm that are incapable of fertilizing an oocyte naturally. In a previous study where we undertook a whole exome screen to define novel genetic causes of globozoospermia, we identified homozygous mutations in the gene PDCD2L. Two brothers carried a p.(Leu225Val) variant predicted to introduce a novel splice donor site, thus presenting PDCD2L as a potential regulator of male fertility. In this study, we generated a Pdcd2l knockout mouse to test its role in male fertility. Contrary to the phenotype predicted from its testis-enriched expression pattern, Pdcd2l null mice died during embryogenesis. Specifically, we identified that Pdcd2l is essential for post-implantation embryonic development. Pdcd2l^–/– embryos were resorbed at embryonic days 12.5-17.5 and no knockout pups were born, while adult heterozygous Pdcd2l males had comparable fertility to wildtype males. To specifically investigate the role of PDCD2L in germ cells, we employed Drosophila melanogaster as a model system. Consistent with the mouse data, global knockdown of trus, the fly ortholog of PDCD2L, resulted in lethality in flies at the third instar larval stage. However, germ cell-specific knockdown with two germ cell drivers did not affect male fertility. Collectively, these data suggest that PDCD2L is not essential for male fertility. By contrast, our results demonstrate an evolutionarily conserved role of PDCD2L in development.

Globozoospermia 是一种罕见的男性不育症，男性会产生圆头精子，这些精子不能自然地使卵母细胞受精。在之前的一项研究中，我们进行了一个完整的外显子组筛选来定义球精子症的新遗传原因，我们在PDCD2L基因中发现了纯合突变。两兄弟携带一个 p.(Leu225Val) 变体，预计会引入一个新的剪接供体位点，从而表明PDCD2L是男性生育能力的潜在调节因子。在这项研究中，我们生成了Pdcd2l敲除小鼠来测试其在雄性生育能力中的作用。与其富含睾丸的表达模式预测的表型相反，Pdcd2l缺失小鼠在胚胎发生过程中死亡。具体来说，我们发现Pdcd2l对植入后胚胎发育至关重要。Pdcd2l ^–/–胚胎在胚胎发育第 12.5-17.5 天被吸收，没有基因敲除幼崽出生，而成年杂合子Pdcd2l雄性具有与野生型雄性相当的生育能力。为了专门研究 PDCD2L 在生殖细胞中的作用，我们采用果蝇作为模型系统。与小鼠数据一致，trus 的全球击倒，即 PDCD2L的果蝇直向同源物，导致三龄幼虫阶段的果蝇死亡。然而，使用两个生殖细胞驱动因子的生殖细胞特异性敲低并不影响男性生育能力。总的来说，这些数据表明PDCD2L对男性生育能力不是必需的。相比之下，我们的结果证明了PDCD2L在发育中的进化保守作用。