• PMID: 24762434
• Gene Name: GAS6
• Condition: Male infertility
• Association: Evaluation of molecular markers in the testes of patients with nonobstructive azoospermia (NOA) revealed enhanced expression of CYP19, GAS6, and AXL, which suggests that the AROM+ mouse model reflects human infertility. Together, these results suggest tha
• Population size: 186
• Population details: 186 (47 NOA, 11 OA, 20 NOA, 10 OA, 18 healthy Chinese men with children, 12 healthy men who were semen donors, 15 healthy volunteers, 42 Chinese patients with NOA, 11 Chinese patients with OA)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Male infertility

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

Yu W, Zheng H, Lin W, Tajima A, Zhang Y, Zhang X, Zhang H, Wu J, Han D, Rahman NA, Korach KS, Gao GF, Inoue I, Li X.

Male infertility accounts for almost half of infertility cases worldwide. A subset of infertile men exhibit reduced testosterone and enhanced levels of estradiol (E2), though it is unclear how increased E2 promotes deterioration of male fertility. Here, we utilized a transgenic mouse strain that overexpresses human CYP19, which encodes aromatase (AROM+ mice), and mice with knockout of Esr1, encoding estrogen receptor α (ERαKO mice), to analyze interactions between viable Leydig cells (LCs) and testicular macrophages that may lead to male infertility. In AROM+ males, enhanced E2 promoted LC hyperplasia and macrophage activation via ERα signaling. E2 stimulated LCs to produce growth arrest-specific 6 (GAS6), which mediates phagocytosis of apoptotic cells by bridging cells with surface exposed phosphatidylserine (PS) to macrophage receptors, including the tyrosine kinases TYRO3, AXL, and MER. Overproduction of E2 increased apoptosis-independent extrusion of PS on LCs, which in turn promoted engulfment by E2/ERα-activated macrophages that was mediated by AXL-GAS6-PS interaction. We further confirmed E2-dependant engulfment of LCs by real-time 3D imaging. Furthermore, evaluation of molecular markers in the testes of patients with nonobstructive azoospermia (NOA) revealed enhanced expression of CYP19, GAS6, and AXL, which suggests that the AROM+ mouse model reflects human infertility. Together, these results suggest that GAS6 has a potential as a clinical biomarker and therapeutic target for male infertility. FAU - Yu, Wanpeng AU - Yu W FAU - Zheng, Han AU - Zheng H FAU - Lin, Wei AU - Lin W FAU - Tajima, Astushi AU - Tajima A FAU - Zhang, Yong AU - Zhang Y FAU - Zhang, Xiaoyan AU - Zhang X FAU - Zhang, Hongwen AU - Zhang H FAU - Wu, Jihua AU - Wu J FAU - Han, Daishu AU - Han D FAU - Rahman, Nafis A AU - Rahman NA FAU - Korach, Kenneth S AU - Korach KS FAU - Gao, George Fu AU - Gao GF FAU - Inoue, Ituro AU - Inoue I