FSHR-mTOR-HIF1 signaling alleviates mouse follicles from AMPK-induced atresia
Longping Liu,
Ming Hao,
Jianyun Zhang,
Ziqi Chen,
Jiaqi Zhou,
Chao Wang,
Hua Zhang,
Jianbin Wang
Affiliations
Longping Liu
School of Life Sciences, Tsinghua University, Beijing 100084, China
Ming Hao
School of Life Sciences, Tsinghua University, Beijing 100084, China
Jianyun Zhang
Department of Oral Pathology, Peking University School, Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials, Digital Medical Devices, Beijing 100081, P.R. China
Ziqi Chen
State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
Jiaqi Zhou
State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
Chao Wang
State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
Hua Zhang
State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
Jianbin Wang
School of Life Sciences, Tsinghua University, Beijing 100084, China; Corresponding author
Summary: The majority of activated ovarian follicles undergo atresia during reproductive life in mammals, and only a small number of follicles are ovulated. Though hormone treatment has been widely used to promote folliculogenesis, the molecular mechanism behind follicle selection and atresia remains under debate due to inconsistency among investigation models. Using a high-throughput molecular pathology strategy, we depicted a transcriptional atlas of mouse follicular granulosa cells (GCs) under physiological condition and obtained molecular signatures in healthy and atresia GCs during development. Functional results revealed hypoxia-inducible factor 1 (HIF1) as a major effector downstream of follicle-stimulating hormone (FSH), and HIF1 activation is essential for follicle growth. Energy shortage leads to prevalent AMP-activated protein kinase (AMPK) activation and drives follicular atresia. FSHR-mTOR-HIF1 signaling helps follicles escape from the atresia fate, while energy stress persists. Our work provides a comprehensive understanding of the molecular network behind follicle selection and atresia under physiological condition.
