CREB activity is required for mTORC1 signaling-induced primordial follicle activation in mice
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ORIGINAL PAPER
CREB activity is required for mTORC1 signaling‑induced primordial follicle activation in mice Jia Li1 · Yu Zhang1 · Nana Zheng1 · Biao Li1 · Jing Yang1 · Chunyu Zhang2 · Guoliang Xia1 · Meijia Zhang1,2 Accepted: 26 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract In mammals, progressive activation of primordial follicles is essential for maintenance of the reproductive lifespan. Several reports have demonstrated that mitogen-activated protein kinases 3 and 1 (MAPK3/1)–mammalian target of rapamycin complex 1 (mTORC1) signaling in pre-granulosa cells promotes primordial follicle activation by increasing KIT ligand (KITL) expression and then stimulating phosphatidylinositol 3 kinase signaling in oocytes. However, the mechanism of mTORC1 signaling in the promotion of KITL expression is unclear. Immunofluorescence staining results showed that phosphorylated cyclic AMP response element-binding protein (CREB) was mainly expressed in pre-granulosa cells. The CREB inhibitor KG-501 and CREB knockdown by Creb siRNA significantly suppressed primordial follicle activation, reduced pre-granulosa cell proliferation and dramatically increased oocyte apoptosis. Western blotting results demonstrated that both the MAPK3/1 inhibitor U0126 and mTORC1 inhibitor rapamycin significantly decreased the levels of phosphorylated CREB, indicating that MAPK3/1–mTORC1 signaling is required for CREB activation. Furthermore, CREB could bind to the Kitl promoter region, and KG-501 significantly decreased the expression levels of KITL. In addition, KG-501 and CREB knockdown significantly decreased the levels of phosphorylated Akt, leading to a reduced number of oocytes with Foxo3a nuclear export. KG-501 also inhibited bpV (HOpic)-stimulated primordial follicle activation. Taken together, the results show that CREB is required for MAPK3/1–mTORC1 signaling-promoted KITL expression followed by the activation of primordial follicles. Keywords CREB · Primordial follicle activation · mTORC1 · KITL
Introduction In mammals, the maintenance of the female reproductive lifespan depends on the primordial follicle pool (Hirshfield 1991; McGee and Hsueh 2000), which is non-renewable (Zhang et al. 2013, 2015). Only a minority of primordial follicles are progressively activated into the growing follicle pool in each wave (Broekmans et al. 2007; McGee and Hsueh 2000), subsequently developing into secondary, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00418-020-01888-4) contains supplementary material, which is available to authorized users. * Meijia Zhang [email protected]; [email protected] 1
State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, P.R. China
School of Medicine, South China University of Technology, Guangzhou 510006, P.R. China
2
antral and preovulatory follicles under follicle-stimulating hormone (FSH) stimulation (Rimon-Dahari et al. 2016; Zeleznik 2004). Lutei
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