PMID- 33291075
OWN - NLM
STAT- MEDLINE
DCOM- 20210507
LR  - 20211204
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 13
IP  - 1
DP  - 2020 Dec 3
TI  - The endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein 
      kinase G pathway activates primordial follicles.
PG  - 1096-1119
LID - 10.18632/aging.202235 [doi]
AB  - In mammals, the well-organized activation of quiescent primordial follicles is 
      pivotal for female reproductive reserve. In the present study, we examined the 
      mechanisms underlying primordial follicle activation in mice. We found that 
      endothelial nitric oxide synthase (eNOS) and its downstream effectors, cyclic 
      guanosine monophosphate (cGMP) and cGMP-dependent protein kinase G (PKG), were 
      expressed in pre-granulosa cells and promoted primordial follicle activation, 
      oocyte growth and granulosa cell proliferation in neonatal ovaries. Mammalian 
      target of rapamycin (mTOR) colocalized with PKG in pre-granulosa cells and was 
      essential for eNOS/cGMP/PKG pathway-induced primordial follicle activation. The 
      eNOS/cGMP/PKG pathway was found to stabilize mTOR protein. The mRNA levels of 
      F-box and WD repeat domain containing 7 (FBXW7), an E3 ubiquitin ligase, 
      correlated negatively with mTOR protein levels in neonatal ovaries. FBXW7 bound 
      to and destabilized mTOR protein in pre-granulosa cells in a 
      ubiquitin/proteasome-dependent manner. However, agonists of the eNOS/cGMP/PKG 
      pathway reduced FBXW7 mRNA levels. FBXW7 overexpression suppressed primordial 
      follicle activation and prevented the eNOS/cGMP/PKG pathway from activating 
      primordial follicles and stabilizing mTOR protein. These findings demonstrate 
      that the eNOS/cGMP/PKG pathway activates primordial follicles by suppressing 
      FBXW7-induced ubiquitination of mTOR in mice.
FAU - Zhao, Peikun
AU  - Zhao P
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Song, Zidai
AU  - Song Z
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Wang, Yan
AU  - Wang Y
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Cai, Han
AU  - Cai H
AD  - Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College 
      of Xiamen University, Xiamen, Fujian, China.
FAU - Du, Xiaoyan
AU  - Du X
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Li, Changlong
AU  - Li C
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Lv, Jianyi
AU  - Lv J
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Liu, Xin
AU  - Liu X
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Guo, Meng
AU  - Guo M
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
FAU - Chen, Zhenwen
AU  - Chen Z
AD  - Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of 
      Basic Medical Sciences, Capital Medical University, Beijing, People’s 
      Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201203
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
RN  - 0 (F-Box-WD Repeat-Containing Protein 7)
RN  - 0 (Fbxw7 protein, mouse)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (FoxO3 protein, mouse)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I)
RN  - EC 2.7.11.12 (Prkg1 protein, mouse)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Cell Proliferation
MH  - Cyclic GMP/*metabolism
MH  - Cyclic GMP-Dependent Protein Kinase Type I/*metabolism
MH  - F-Box-WD Repeat-Containing Protein 7/metabolism
MH  - Female
MH  - Forkhead Box Protein O3/metabolism
MH  - Granulosa Cells/*metabolism
MH  - Mice
MH  - Nitric Oxide Synthase Type III/*metabolism
MH  - Oocytes/growth & development/*metabolism
MH  - Organ Culture Techniques
MH  - Ovarian Follicle/growth & development/*metabolism
MH  - Ovary/*metabolism
MH  - Protein Transport
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Ubiquitination
PMC - PMC7835019
OTO - NOTNLM
OT  - FBXW7
OT  - eNOS/cGMP/PKG pathway
OT  - mTOR
OT  - primordial follicle activation
OT  - ubiquitination
COIS- CONFLICTS OF INTEREST: The authors declare that they do not have any conflicts of 
      interests.
EDAT- 2020/12/09 06:00
MHDA- 2021/05/08 06:00
PMCR- 2021/01/15
CRDT- 2020/12/08 20:13
PHST- 2020/05/02 00:00 [received]
PHST- 2020/10/20 00:00 [accepted]
PHST- 2020/12/09 06:00 [pubmed]
PHST- 2021/05/08 06:00 [medline]
PHST- 2020/12/08 20:13 [entrez]
PHST- 2021/01/15 00:00 [pmc-release]
AID - 202235 [pii]
AID - 10.18632/aging.202235 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2020 Dec 3;13(1):1096-1119. doi: 10.18632/aging.202235. Epub 
      2020 Dec 3.