(36) SIK3 in the Ovarian Theca Cells is Essential for Fertility

Emily T. Hayes¹; Mariam Hassan¹; Oliwia Lakomy¹; Carlos Stocco¹

1. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United States

Abstract Text:

Recently, the salt-inducible kinases (SIKs) have emerged as critical regulators of female fertility. The three isoforms, SIK1, SIK2, and SIK3, are all serine-threonine kinases that form a subfamily of the AMPK-related kinases. Interestingly, global knockouts of SIK2 and SIK3, as well as knockouts specific to the estrogen-producing granulosa cells of the ovarian follicle, revealed differential roles: SIK2 is a negative regulator and SIK3 is a positive regulator of follicle development and steroidogenesis. The global knockout of SIK3 is especially dramatic, resulting in female infertility, stunted follicle growth, gonadotropin resistance, and premature ovarian failure. However, where SIK3 acts in the ovary to provide essential support for female fertility is unknown. Considering the follicle growth defects, reminiscent of androgen excess and androgen deficiency, we hypothesized that SIK3 regulates fertility via actions in the theca cells, the androgen-producing cells of the follicle. To investigate this, a SIK3 theca cell-specific knockout mouse model was generated using the Cre-Lox system in which Cre recombinase was expressed downstream of the Cyp17a1 promoter. Strikingly, these mice were infertile, producing no litters over six months of continuous breeding. Further, in vitro knockdown of SIK3 in primary mouse theca cells blocks Cyp17a1 expression induced by luteinizing hormone, suggesting that SIK3 plays a critical role in androgen synthesis. Previously, our group showed that SIK2 global knockout mice have significantly increased serum testosterone, again suggesting opposing roles of SIK2 and SIK3 in the ovary. This data provides novel insight into the role of SIK3 in fertility, which hopes to inform future work into understanding whether SIK3 can be targeted for treating ovarian pathophysiology or developing new contraceptives.