Myotubularin related protein 7 is essential for the spermatogonial stem cell homeostasis via PI3K/AKT signaling

Zhao, Dan; Shen, Cong; Gao, Tingting; Li, Hong; Guo, Yueshuai; Li, Feng; Liu, Chenchen; Liu, Yuanyuan; Chen, Xia; Zhang, Xi; Wu, Yangyang; Yu, Yi; Lin, Meng Liang; Yan, Yuan; Chen, Xiaofang; Huang, Xiaoyan; Yang, Shenmin; Yu, Jun; Zhang, Jun; Zheng, Bo

doi:10.1080/15384101.2019.1661174

Cited by 25 publications

(18 citation statements)

References 56 publications

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“…Cells were harvested, fixed in 4% ( w / v ) paraformaldehyde (PFA), blocked with 2% bovine serum albumin (BSA) ( w / v ) (Sigma) for 45 min at RT, and incubated with primary antibodies ( Supplementary Table 1 ) overnight at 4°C according to a previously reported protocol ( Zheng et al, 2018 ; Zhao et al, 2019 ). Next, the cells were rinsed with PBS and incubated with Alexa Fluor-conjugated secondary antibodies (Thermo Scientific) for 45 min.…”

Section: Methodsmentioning

confidence: 99%

BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway

et al. 2021

Front. Cell Dev. Biol.

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Testosterone biosynthesis progressively decreases in aging males primarily as a result of functional changes to Leydig cells. Despite this, the mechanisms underlying steroidogenesis remain largely unclear. Using gene knock-out approaches, we and others have recently identified Bmi1 as an anti-aging gene. Herein, we investigate the role of BMI1 in steroidogenesis using mouse MLTC-1 and primary Leydig cells. We show that BMI1 can positively regulate testosterone production. Mechanistically, in addition to its known role in antioxidant activity, we also report that p38 mitogen-activated protein kinase (MAPK) signaling is activated, and testosterone levels reduced, in BMI1-deficient cells; however, the silencing of the p38 MAPK pathway restores testosterone production. Furthermore, we reveal that BMI1 directly binds to the promoter region of Map3k3, an upstream activator of p38, thereby modulating its chromatin status and repressing its expression. Consequently, this results in the inhibition of the p38 MAPK pathway and the promotion of steroidogenesis. Our study uncovered a novel epigenetic mechanism in steroidogenesis involving BMI1-mediated gene silencing and provides potential therapeutic targets for the treatment of hypogonadism.

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Section: Methodsmentioning

confidence: 99%

BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway

et al. 2021

Front. Cell Dev. Biol.

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“…Apoptotic cells were detected by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL; BrightRed Apoptosis Detection Kit, Vazyme), as previously described ( Zhao et al, 2019 ). Briefly, BM-MSCs were fixed with 4% (w/v) PFA and treated with proteinase K (10 μg/ml) for 10 min at room temperature, followed by incubation with BrightRed Labeling Buffer for 45 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

INTS7–ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress

et al. 2021

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Increased adipocyte and decreased osteoblast differentiation, combined with the ectopic proliferation of bone marrow mesenchymal stem cells (BM-MSCs), represent the primary causes of osteoporosis. The dysregulation of numerous intracellular bioactive factors is responsible for the aberrant differentiation and growth of BM-MSCs. In this study, we focused on a new stimulative factor, integrator complex subunit 7 (INTS7), and its cooperative protein ATP-binding cassette subfamily D member 3 (ABCD3)/high-density lipoprotein-binding protein (HDLBP) in mouse BM-MSCs. We aimed to uncover the effects of the INTS7–ABCD3/HDLBP interaction on BM-MSC biological behaviors and the potential mechanism underlying these effects. Functional in vitro experiments showed that the suppression of the INTS7–ABCD3 interaction rather than HDLBP could impair BM-MSC proliferation and induce cell apoptosis. Moreover, Alizarin Red S and Oil Red O staining, respectively, revealed that INTS7 and ABCD3 knockdown but not HDLBP knockdown could decrease osteoblastic differentiation and accelerate the adipogenic differentiation of BM-MSCs. Mechanistically, reactive oxygen species (ROS) and histone γ-H2AX quantities significantly increased, whereas the levels of antioxidants declined due to INTS7 and ABCD3 inhibition in BM-MSCs. These findings indicated that the suppression of oxidative stress could be involved in the INTS7/ABCD3 co-regulatory mechanisms for BM-MSC proliferation and differentiation, identifying new potential candidates for osteoporosis therapy.

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“…Testicular lysates and immunoprecipitated proteins were separated by SDS-PAGE and transferred onto a polyvinylidene difluoride membrane as previously reported (31,32). The membrane was blocked and incubated overnight at 4 ℃ with the indicated primary antibodies (Table S1).…”

Section: Western Blotmentioning

confidence: 99%

E3 ubiquitin ligase ASB17 is required for spermiation in mice

Shen

Zhou

et al. 2021

Transl Androl Urol

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Background: A major goal of spermiation is to degrade the apical ectoplasmic specialization (ES) junction between Sertoli cells and elongating spermatids in preparation for the eventual disengagement of spermatids into the lumen. E3 ubiquitin ligases mediate the process of ubiquitination and the subsequent proteasomal degradation, but their specific role during spermiation remains largely unexplored.Methods: Ankyrin repeat and SOCS box protein 17 (Asb17)-knockout mice were generated via a CRISPR/Cas9 approach. Epididymal sperm parameters were assessed by a computer-assisted sperm analysis (CASA) system, and morphological analysis of testicular tissues were performed based on histological and immunostaining staining, and transmission electron microscopy (TEM). The interactions between ASB17 and Espin (ESPN) were predicted by HawkDock server and validated through protein pull-down and immunoprecipitation assays.Results: We report that ASB17, an E3 ligase, is required for the completion of spermiation and that mice lacking Asb17 are oligozoospermic owing to spermiation failure. ASB17-deficient mice are fertile; however, spermatids exhibit a disorganized ES junction, resulting in retention within the seminiferous epithelium.Mechanistically, ASB17 deficiency leads to excess accumulation of ESPN, an actin-binding essential structural component of the ES. We determined that ASB17 regulates the removal of the ES through ubiquitin mediated protein degradation of ESPN.Conclusions: In summary, our study describes a role for ASB17 in the regulation of cell-cell junctions between germ cells and somatic cells in the testis. These findings establish a novel mechanism for the regulatory role of E3 ligases during spermatogenesis.

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Myotubularin related protein 7 is essential for the spermatogonial stem cell homeostasis via PI3K/AKT signaling

Cited by 25 publications

References 56 publications

BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway

BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway

INTS7–ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress

E3 ubiquitin ligase ASB17 is required for spermiation in mice

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