Department of Genetics, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Adv. 2020 Oct 30;6(44). doi: 10.1126/sciadv.abc5580. Print 2020 Oct.
Oocyte numbers, a critical determinant of female reproductive fitness, are highly regulated, yet the mechanisms underlying this regulation remain largely undefined. In the gonad, RAS/extracellular signal-regulated kinase (ERK) signaling regulates oocyte numbers; mechanisms are unknown. We show that the RAS/ERK pathway phosphorylates meiotic chromosome axis protein HTP-1 at serine-325 to control chromosome dynamics and regulate oocyte number. Phosphorylated HTP-1(S325) accumulates in vivo in an ERK-dependent manner in early-mid pachytene stage germ cells and is necessary for synaptonemal complex extension and/or maintenance. Lack of HTP-1 phosphorylation leads to asynapsis and persistence of meiotic double-strand breaks, causing delayed meiotic progression and reduced oocyte number. In contrast, early onset of ERK activation causes precocious meiotic progression, resulting in increased oocyte number, which is reversed by removal of HTP-1 phosphorylation. The RAS/ERK/HTP-1 signaling cascade thus functions to monitor formation and maintenance of synapsis for timely resolution of double-strand breaks, oocyte production, and reproductive fitness.
卵母细胞数量是女性生殖能力的一个关键决定因素，其受到高度调控，但调控机制在很大程度上仍未得到明确。在性腺中，RAS/细胞外信号调节激酶（ERK）信号通路调节卵母细胞数量；其具体机制尚不清楚。我们发现，RAS/ERK 通路通过丝氨酸 325 位磷酸化减数分裂染色体轴蛋白 HTP-1，从而控制染色体动态，调节卵母细胞数量。磷酸化的 HTP-1（S325）以 ERK 依赖性方式在早-中期生精细胞中在体内积累，对联会复合体的延伸和/或维持是必需的。缺乏 HTP-1 的磷酸化会导致联会缺失和减数分裂双链断裂的持续存在，导致减数分裂进程延迟和卵母细胞数量减少。相比之下，ERK 的早期激活会导致减数分裂进程过早开始，从而导致卵母细胞数量增加，但通过去除 HTP-1 的磷酸化可以逆转这一现象。因此，RAS/ERK/HTP-1 信号级联反应的功能是监测联会的形成和维持，以实现双链断裂的及时解决、卵母细胞的产生和生殖能力。
