Department of Physiology and Biophysics, School of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Université Paris Cité, CNRS, INSERM, Institut Cochin, F-75014 Paris, France.
Endocrinology. 2024 Aug 27;165(10). doi: 10.1210/endocr/bqae107.
Salt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles. This study hypothesizes that SIK2 and SIK3 differentially regulate follicle growth and fertility via contrasting actions in the granulosa cells (GCs), the somatic cells of the follicle. Therefore, SIK2 or SIK3 GC-specific knockdown (SIK2GCKD and SIK3GCKD, respectively) mice were generated by crossing SIK floxed mice with Cyp19a1pII-Cre mice. Fertility studies revealed that pup accumulation over 6 months and the average litter size of SIK2GCKD mice were similar to controls, although in SIK3GCKD mice were significantly lower compared to controls. Compared to controls, gonadotropin stimulation of prepubertal SIK2GCKD mice resulted in significantly higher serum estradiol levels, whereas SIK3GCKD mice produced significantly less estradiol. Cyp11a1, Cyp19a1, and StAR were significantly increased in the GCs of gonadotropin-stimulated SIK2GCKD mice. However, Cyp11a1 and StAR remained significantly lower than controls in SIK3GCKD mice. Interestingly, Cyp19a1 stimulation in SIK3GCKD was not statistically different compared to controls. Superovulation resulted in SIK2GCKD mice ovulating significantly more oocytes, whereas SIK3GCKD mice ovulated significantly fewer oocytes than controls. Remarkably, SIK3GCKD superovulated ovaries contained significantly more preantral follicles than controls. SIK3GCKD ovaries contained significantly more apoptotic cells and fewer proliferating cells than controls. These data point to the differential regulation of GC function and follicle development by SIK2 and SIK3 and supports the therapeutic potential of targeting these kinases for treating infertility or developing new contraceptives.
盐诱导激酶（SIKs）是丝氨酸/苏氨酸激酶家族的一个成员，被发现是雌性生育力的关键决定因素。SIK2 的沉默导致对促性腺激素的排卵反应增加。相比之下，SIK3 敲除导致不育、促性腺激素不敏感以及卵巢中缺乏窦前和排卵前卵泡。本研究假设 SIK2 和 SIK3 通过在颗粒细胞（GC）中的相反作用来差异调节卵泡生长和生育力，GC 是卵泡的体细胞。因此，通过将 SIK 基因敲除小鼠与 Cyp19a1pII-Cre 小鼠杂交，生成 SIK2 或 SIK3GC 特异性敲低（分别为 SIK2GCKD 和 SIK3GCKD）小鼠。生育力研究表明，SIK2GCKD 小鼠在 6 个月内的幼仔积累量和平均窝仔数与对照组相似，尽管 SIK3GCKD 小鼠的幼仔数明显低于对照组。与对照组相比，促性腺激素刺激的青春期前 SIK2GCKD 小鼠的血清雌二醇水平显著升高，而 SIK3GCKD 小鼠的雌二醇水平显著降低。在促性腺激素刺激的 SIK2GCKD 小鼠的 GC 中，Cyp11a1、Cyp19a1 和 StAR 显著增加。然而，在 SIK3GCKD 小鼠中，Cyp11a1 和 StAR 仍明显低于对照组。有趣的是，与对照组相比，SIK3GCKD 中的 Cyp19a1 刺激没有统计学差异。超排卵导致 SIK2GCKD 小鼠排卵的卵母细胞明显增多，而 SIK3GCKD 小鼠排卵的卵母细胞明显少于对照组。值得注意的是，SIK3GCKD 超排卵的卵巢中窦前卵泡明显多于对照组。与对照组相比，SIK3GCKD 卵巢中的凋亡细胞明显更多，增殖细胞明显更少。这些数据表明 SIK2 和 SIK3 对 GC 功能和卵泡发育的差异调节，并支持针对这些激酶治疗不育症或开发新避孕药具的治疗潜力。
