Specific deletion of protein phosphatase 6 catalytic subunit in Sertoli cells leads to disruption of spermatogenesis

Wen-Long Lei,Qing-Yuan Sun,Chun-Hui Zhang,Si-Min Sun,Yan Ning,Tie-Gang Meng,Wei-Ping Qian,Yuan-Yuan Li,Yaoting Gui,Zhen-Bo Wang

doi:10.1038/s41419-021-04172-y

Abstract

Protein phosphatase 6 (PP6) is a member of the PP2A-like subfamily, which plays significant roles in numerous fundamental biological activities. We found that PPP6C plays important roles in male germ cells recently. Spermatogenesis is supported by the Sertoli cells in the seminiferous epithelium. In this study, we crossed Ppp6cF/F mice with AMH-Cre mice to gain mutant mice with specific depletion of the Ppp6c gene in the Sertoli cells. We discovered that the PPP6C cKO male mice were absolutely infertile and germ cells were largely lost during spermatogenesis. By combing phosphoproteome with bioinformatics analysis, we showed that the phosphorylation status of β-catenin at S552 (a marker of adherens junctions) was significantly upregulated in mutant mice. Abnormal β-catenin accumulation resulted in impaired testicular junction integrity, thus led to abnormal structure and functions of BTB. Taken together, our study reveals a novel function for PPP6C in male germ cell survival and differentiation by regulating the cell-cell communication through dephosphorylating β-catenin at S552.

Highlights

Spermatogenesis is an intricate developmental process by which spermatogonial stem cells (SSCs) renovate and differentiate to produce mature spermatozoa, consisting of three phases: spermatogonial mitosis, spermatocytic meiosis, and spermiogenesis [1]
Unlike other blood-tissue barriers forming by a tight junction (TJ) [8], the blood‐testis barrier (BTB) is constituted by several types of cell-cell junctions, such as TJ, adhesion junction (AJ), gap junction (GJ) and desmosome-like junction, and numerous junctional proteins are involved in the formation of BTB [7]
By combing phosphoproteome with bioinformatics analysis, we showed that the phosphorylation status of β-catenin at S552 was significantly upregulated in conditional knockout (cKO) group. β-catenin abnormal accumulation resulted in impaired testicular junction integrity, led to the abnormal structures and functions of BTB

Summary

Introduction

Spermatogenesis is an intricate developmental process by which spermatogonial stem cells (SSCs) renovate and differentiate to produce mature spermatozoa, consisting of three phases: spermatogonial mitosis, spermatocytic meiosis, and spermiogenesis [1]. Any errors in this process can result in serious outcomes including infertility [2, 3]. Spermiogenesis occur in the apical compartment, whereas SSCs division and differentiation to preleptotene spermatocytes take place in the basal compartment [5, 6]. Unlike other blood-tissue barriers forming by a tight junction (TJ) [8], the BTB is constituted by several types of cell-cell junctions, such as TJ, adhesion junction (AJ), gap junction (GJ) and desmosome-like junction, and numerous junctional proteins are involved in the formation of BTB [7]

Methods

Results

Conclusion