Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2220576120. doi: 10.1073/pnas.2220576120. Epub 2023 Apr 10.
Across species, sperm maturation involves the dramatic reconfiguration of chromatin into highly compact nuclei that enhance hydrodynamic ability and ensure paternal genomic integrity. This process is mediated by the replacement of histones by sperm nuclear basic proteins, also referred to as protamines. In humans, a carefully balanced dosage between two known protamine genes is required for optimal fertility. However, it remains unknown how their proper balance is regulated and how defects in balance may lead to compromised fertility. Here, we show that a nucleolar protein, , a homolog of , mediates the histone-to-protamine transition during spermatogenesis. We find that mutants display nuclear compaction defects during late spermatogenesis due to decreased expression of autosomal protamine genes (including ) and derepression of Y-linked multicopy homologs (), leading to the mutant's known sterility. Overexpression of in a wild-type background is sufficient to cause nuclear compaction defects, similar to mutant, indicating that Mst77Y is a dominant-negative variant interfering with the process of histone-to-protamine transition. Interestingly, ectopic overexpression of caused decompaction of X-bearing spermatids nuclei more frequently than Y-bearing spermatid nuclei, although this did not greatly affect the sex ratio of offspring. We further show that regulates these protamine genes at the step of transcript polyadenylation. We conclude that the regulation of protamines mediated by , ensuring the expression of functional ones while repressing dominant-negative ones, is critical for male fertility.
在不同物种中，精子成熟涉及到染色质的剧烈重排，形成高度紧凑的核，从而增强了水动力能力并确保了父本基因组的完整性。这个过程是通过由精子核碱性蛋白（也称为鱼精蛋白）取代组蛋白来介导的。在人类中，需要两种已知的鱼精蛋白基因之间的精细平衡剂量才能实现最佳生育能力。然而，其适当平衡的调节方式以及平衡缺陷如何导致生育能力受损仍不清楚。在这里，我们表明核仁蛋白 是 同源物，在精子发生过程中介导组蛋白向鱼精蛋白的转变。我们发现，由于常染色体鱼精蛋白基因（包括 ）的表达减少和 Y 染色体多拷贝 同源物（）的去抑制， 突变体在晚期精子发生中显示出核浓缩缺陷，导致突变体的已知不育。在野生型背景下过度表达 足以引起核浓缩缺陷，类似于 突变体，表明 Mst77Y 是一种显性负变体，干扰组蛋白向鱼精蛋白转变的过程。有趣的是，尽管这并没有极大地影响后代的性别比例，但 的异位过表达导致 X 染色体携带的精母细胞核解浓缩的频率比 Y 染色体携带的精母细胞核更高。我们进一步表明， 在转录多聚腺苷酸化步骤调节这些鱼精蛋白基因。我们得出结论， 介导的鱼精蛋白调节确保了功能性鱼精蛋白的表达，同时抑制了显性负变体，这对于男性生育能力至关重要。
