DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation  

作　　者：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 

机构地区：[1]Institute of Women,Children and Reproductive Health,Shandong University,Jinan 250012,China [2]State Key Laboratory of Reproductive Medicine and Offspring Health,Jinan 250012,China [3]Key laboratory of Reproductive Endocrinology of Ministry of Education,Shandong University,Jinan 250012,China [4]Shandong Key Laboratory of Reproductive Medicine,Shandong University,Jinan 250012,China [5]Shandong Provincial Clinical Research Center for Reproductive Health,Jinan 250012,China [6]National Research Center for Assisted Reproductive Technology and Reproductive Genetics,Shandong University,Jinan 250012,China [7]The Affiliated Suzhou Hospital of Nanjing Medical University,Suzhou Municipal Hospital,Nanjing Medical University,Suzhou 215008,China [8]Gusu School,Nanjing Medical University,Suzhou 215000,China [9]Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510080,China [10]Guangdong-Hong Kong Metabolism&Reproduction Joint Laboratory,Guangdong Second Provincial General Hospital,Guangzhou 510317,China [11]Reproductive Medicine Center,Guangdong Second Provincial General Hospital,Guangzhou 510317,China [12]Research Unit of Gametogenesis and Health of ART-Offspring,Chinese Academy of Medical Sciences(No.2021RU001),Jinan 250012,China [13]Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics,Shanghai 200127,China [14]Center for Reproductive Medicine,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China

出　　处：《Science China(Life Sciences)》2024年第8期1620-1634,共15页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China(2021YFC2700400);the Basic Science Center Program(31988101);the National Natural Science Foundation of China(82071606,31871509,82201800,82071610);the Shandong Provincial Key Research and Development Program(2020ZLYS02);Ferring Institute of Reproductive Medicine(FIRMA180310).

摘　　要：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 development 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.

关 键 词：PCOS DENND1A FSHR ovarian granulosa cells 

分 类 号：R711.75[医药卫生—妇产科学]