title: MAPK3/1 participates in the activation of primordial follicles through mTORC1-KITL signaling.
abstract: The majority of ovarian primordial follicles are preserved in a dormant state to maintain the female reproductive lifespan, and only a few primordial follicles are activated to enter the growing follicle pool in each wave. Recent studies have shown that primordial follicular activation depends on mammalian target of rapamycin complex 1 (mTORC1)-KIT ligand (KITL) signaling in pre-granulosa cells and its receptor (KIT)-phosphoinositol 3 kinase (PI3K) signaling in oocytes. However, the upstream regulator of mTORC1 signaling is unclear. The results of the present study showed that the phosphorylated mitogen-activated protein kinase3/1 (MAPK3/1) protein is expressed in some primordial follicles and all growing follicles. Culture of 3 days post-parturition (dpp) ovaries with the MAPK3/1 signaling inhibitor U0126 significantly reduced the number of activated follicles and was accompanied by dramatically reduced granulosa cell proliferation and increased oocyte apoptosis. Western blot and immunofluorescence analyses showed that U0126 significantly decreased the phosphorylation levels of Tsc2, S6K1, and rpS6 and the expression of KITL, indicating that U0126 inhibits mTORC1-KITL signaling. Furthermore, U0126 decreased the phosphorylation levels of Akt, resulting in a decreased number of oocytes with Foxo3 nuclear export. To further investigate MAPK3/1 signaling in primordial follicle activation, we used phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor bpV(HOpic) to promote primordial follicle activation. In this model, U0126 also inhibited the activation of primordial follicles and mTORC1 signaling. Thus, these results suggest that MAPK3/1 participates in primordial follicle activation through mTORC1-KITL signaling.
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Nana
authors.initials: N
authors.lastname: Zheng
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xia
authors.affiliation: State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, People's Republic of China.
authors.forename: Meijia
authors.identifier: http://orcid.org/0000-0001-7803-3054
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D009865:Oocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: MAPK3/1; PI3K; mTORC1; primordial follicle activation