Laboratory of Germ Cell Development, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Mamm Genome. 2022 Dec;33(4):590-605. doi: 10.1007/s00335-022-09954-z. Epub 2022 May 20.
Aneuploidy (abnormal chromosome number) accompanies reduced ovarian function in humans and mice, but the reasons behind this concomitance remain underexplored. Some variants in the human gene encoding histone-3-lysine-4,36-trimethyltransferase PRDM9 are associated with aneuploidy, and other variants with ovarian function reduced by premature ovarian failure (POF), but no link between POF and aneuploidy has been revealed. SHR/OlaIpcv rat females lacking PRDM9 manifest POF-a reduced follicle number, litter size, and reproductive age. Here, we explored this model to test how POF relates to oocyte euploidy. The mutant rat females displayed increased oocyte aneuploidy and embryonic death of their offspring compared to controls. Because rat PRDM9 positions meiotic DNA breaks, we investigated the repair of these breaks. Fertile control rodents carry pachytene oocytes with synapsed homologous chromosomes and repaired breaks, while sterile Prdm9-deficient mice carry pachytene-like oocytes with many persisting breaks and asynapsed chromosomes. However, most PRDM9-lacking rat oocytes displayed a few persisting breaks and non-homologous synapsis (NHS). HORMAD2 protein serves as a barrier to sister-chromatid repair and a signal for the synapsis and DNA repair checkpoints. NHS but not asynapsis was associated with HORMAD2 levels similar to the levels on rat pachytene chromosomes with homologous synapsis. NHS was accompanied by crossing-over decreased below the minimum that is essential for euploidy. We argue that the increased mutant rat aneuploidy is due to NHS, which allows some oocytes to pass meiotic checkpoints without one crossing-over per chromosomal pair, leading to segregation errors, and thereby NHS links POF to aneuploidy.
非整倍体（染色体数目异常）伴随着人类和小鼠卵巢功能下降，但这种伴随的原因仍未得到充分探索。人类编码组蛋白-3-赖氨酸-4,36-三甲基转移酶 PRDM9 的基因的一些变体与非整倍体有关，而其他变体与卵巢功能减退的早发性卵巢功能衰竭（POF）有关，但 POF 与非整倍体之间没有联系。缺乏 PRDM9 的 SHR/OlaIpcv 雌性大鼠表现出 POF-卵泡数量减少、产仔数减少和生殖年龄减少。在这里，我们探索了这个模型，以测试 POF 与卵母细胞非整倍体的关系。与对照组相比，突变型大鼠雌性的卵母细胞非整倍体增加，后代胚胎死亡。因为大鼠 PRDM9 定位减数分裂 DNA 断裂，所以我们研究了这些断裂的修复。可育的对照啮齿动物携带具有同源染色体联会的粗线期卵母细胞和修复的断裂，而不育的 Prdm9 缺陷型小鼠携带具有许多持续存在的断裂和未联会染色体的粗线期样卵母细胞。然而，大多数缺乏 PRDM9 的大鼠卵母细胞显示出少数持续存在的断裂和非同源联会（NHS）。HORMAD2 蛋白作为姐妹染色单体修复的障碍和同源联会和 DNA 修复检查点的信号。NHS 而不是未联会与 HORMAD2 水平相关，类似于具有同源联会的大鼠粗线期染色体的水平。NHS 伴随着交叉减少到低于使卵母细胞保持非整倍体所必需的最低水平。我们认为，突变型大鼠非整倍体的增加是由于 NHS，它允许一些卵母细胞通过减数分裂检查点而无需每对染色体发生一次交叉，导致分离错误，从而 NHS 将 POF 与非整倍体联系起来。
