Deletion of the tyrosine phosphatase Shp2 in Sertoli cells causes infertility in mice.
The male's ability to reproduce is completely dependent on Sertoli cells. However, the mechanisms governing the functional integrity of Sertoli cells have remained largely unexplored. Here, we demonstrate that deletion of Shp2 in Sertoli cells results in infertility in mice. In Shp2 knockout mice (SCSKO), a normal population of Sertoli cells was observed, but the blood-testis barrier (BTB) was not formed. Shp2 ablation initiated the untimely and excessive differentiation of spermatogonial stem cells (SSCs) by disturbing the expression of paracrine factors. As a consequence, the process of spermatogenesis was disrupted, and the germ cells were depleted. Furthermore, Shp2 deletion impaired the cell junctions of the primary Sertoli cells and failed to support the clonal formation of SSCs co-cultured with SCSKO Sertoli cells. As expected, Shp2 restoration largely restores the cell junctions of the primary Sertoli cells and the clonal formation of SSCs. To identify the underlying mechanism, we further demonstrated that the absence of Shp2 suppressed Erk phosphorylation, and thus, the expression of follicle-stimulating hormone (FSH)- and testosterone-induced target genes. These results collectively suggest that Shp2 is a critical signaling protein that is required to maintain Sertoli cell function and could serve as a novel target for male infertility therapies.
School of Physics and Mechanical &Electrical Engineering, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Xiaopeng
X
Hu
1] School of Physics and Mechanical &Electrical Engineering, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China [2] State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Zhenzhou
Z
Tang
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Yang
Y
Li
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Wensheng
W
Liu
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Shuang
S
Zhang
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Bingyan
B
Wang
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Yingpu
Y
Tian
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Yinan
Y
Zhao
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Hao
H
Ran
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Wenjie
W
Liu
Department of Pathology, and Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Gen-Sheng
GS
Feng
School of Physics and Mechanical &Electrical Engineering, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Jianwei
J
Shuai
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Haibin
H
Wang
1] School of Physics and Mechanical &Electrical Engineering, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China [2] State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Zhongxian
Z
Lu
D000818:Animals; D002454:Cell Differentiation; D005640:Follicle Stimulating Hormone / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D012708:Sertoli Cells / Q000166:cytology / Q000201:enzymology*; D013739:Testosterone / Q000502:physiology
D013739:Testosterone; D005640:Follicle Stimulating Hormone; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11