首页|DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation

DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation

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Polycystic ovary syndrome(PCOS)is a complex disorder.Genome-wide association studies(GWAS)have identified several genes associated with this condition,including DENND1A.DENND1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular transport.However,the specific role of DENND1A in reproductive hormone abnormalities and follicle devel-opment disorders in PCOS remain poorly understood.In this study,we investigated DENND1A expression in ovarian granulosa cells(GCs)from PCOS patients and its correlation with hormones.Our results revealed an upregulation of DENND1A expression in GCs from PCOS cases,which was positively correlated with testosterone levels.To further explore the functional implications of DENND1A,we generated a transgenic mouse model overexpressing Dennd1a(TG mice).These TG mice exhibited subfertility,irregular estrous cycles,and increased testosterone production following PMSG stimulation.Additionally,the TG mice displayed diminished responsiveness to FSH,characterized by smaller ovary size,less well-developed follicles,and abnormal expressions of FSH-priming genes.Mechanistically,we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor(FSHR),promoting its internalization and inhibiting recycling.These findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms,thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.

PCOSDENND1AFSHRovarian granulosa cells

Yunde Dou、Rusong Zhao、Han Wu、Zhiheng Yu、Changjian Yin、Jie Yang、Chaoyan Yang、Xiaohua Luan、Yixiao Cheng、Tao Huang、Yuehong Bian、Shan Han、Yuqing Zhang、Xin Xu、Zi-Jiang Chen、Han Zhao、Shigang Zhao

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Institute of Women,.Children and Reproductive Health,Shandong University,Jinan 250012,China

State Key Laboratory of Reproductive Medicine and Offspring Health,Jinan 250012,China

Key laboratory of Reproductive Endocrinology of Ministry of Education,Shandong University,Jinan 250012,China

Shandong Key Laboratory of Reproductive Medicine,Shandong University,Jinan 250012,China

Shandong Provincial Clinical Research Center for Reproductive Health,Jinan 250012,China

National Research Center for Assisted Reproductiv

Research Unit of Gametogenesis and Health of ART-Offspring,Chinese Academy of Medical Sciences(No.2021 RU001),Jinan 250012,China

National Research Center for Assisted Reproductive Technology and Reproductive Genetics,Shandong U

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National Key Research and Development Program of ChinaBasic Science Center ProgramNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShandong Provincial Key Research and Development Program

2021YFC270040031988101820716063187150982201800.820716102020ZLYS02

2024

10.1007/s11427-023-2438-4

中国科学:生命科学(英文版)
中国科学院

中国科学:生命科学(英文版)

CSTPCD
影响因子：0.806
ISSN：1674-7305
年,卷(期)：2024.67(8)