Hakim Bilal Ahmad, Tsatskis Yonit, Zhang Ling, Choi Esther, Zhang Ying, Hodzic Didier, Wu Que, Zhang MuYun, Pashei Maryam, Ha Kyungwon, Brill Julie A, Brieño-Enríquez Miguel Angel, Jurisicova Andrea, McNeill Helen
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell & Systems Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Res Sq. 2025 Aug 4:rs.3.rs-7159889. doi: 10.21203/rs.3.rs-7159889/v1.
Female germ cells must preserve the integrity of their genome and generate genetic diversity via meiotic recombination. This challenging process, which occurs during fetal life, is error prone. Highly conserved checkpoint pathways detect errors in recombination and DNA damage, inducing the death of defective oocytes. Nuclear Envelope Membrane Protein (NEMP) homologs are highly conserved inner nuclear membrane proteins which are critical for fertility in flies, worms, fish and mice, and mechanically support the nuclear envelope. However, why NEMP homologs are required for fertility is still unclear. Using both and mouse models, we establish here that loss of Nemp1 leads to activation of an ATM-CHK2 DNA damage pathway and results in massive loss of oocytes during fetal life. Chemical or genetic inactivation of the ATM-CHK2-p63 pathway reduces oocyte loss, demonstrating its importance upon loss of Nemp1. In the absence of Nemp1 meiotic progression is delayed and DNA damage is increased at zygonema and pachynema stages. Loss of Nemp1 also leads to defects in chromosome synapsis persisting through pachynema. We conclude that Nemp1 is needed for timely and precise execution of meiotic prophase and is crucial for accurate pairing and synapsis, oocyte developmental competence and survival.
雌性生殖细胞必须保持其基因组的完整性，并通过减数分裂重组产生遗传多样性。这个具有挑战性的过程发生在胎儿期，容易出错。高度保守的检查点通路能检测重组和DNA损伤中的错误，诱导有缺陷的卵母细胞死亡。核包膜膜蛋白（NEMP）同源物是高度保守的内核膜蛋白，对果蝇、线虫、鱼类和小鼠的生育能力至关重要，并在机械上支撑核包膜。然而，NEMP同源物为何对生育能力是必需的仍不清楚。利用斑马鱼和小鼠模型，我们在此确定Nemp1的缺失会导致ATM-CHK2 DNA损伤通路的激活，并在胎儿期导致大量卵母细胞丢失。ATM-CHK2-p63通路的化学或基因失活可减少卵母细胞丢失，证明其在Nemp1缺失时的重要性。在没有Nemp1的情况下，减数分裂进程延迟，在偶线期和粗线期DNA损伤增加。Nemp1的缺失还会导致染色体联会缺陷持续到粗线期。我们得出结论，Nemp1是减数分裂前期及时、精确执行所必需的，对准确配对和联会、卵母细胞发育能力和存活至关重要。
