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The Alteration of Rhoa Geranylgeranylation and Ras Farnesylation Breaks the Integrity of the Blood–Testis Barrier and Results

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The Alteration of Rhoa Geranylgeranylation and Ras Farnesylation Breaks the Integrity of the Blood–Testis Barrier and Results Zhu et al. Cell Death and Disease (2019) 10:450 https://doi.org/10.1038/s41419-019-1688-9 Cell Death & Disease ARTICLE Open Access The alteration of RhoA geranylgeranylation and Ras farnesylation breaks the integrity of the blood–testis barrier and results in hypospermatogenesis Ruilou Zhu1,2,JiangnanWang1, Tianxiang Feng1,2,XuechunHu3,ChenJiang1, Xiuxing Wang1,KangLi1,2, Yongjuan Sang1,2,YueHua1,2, Haixiang Sun2,4,BingYao2,3 and Chaojun Li1,2 Abstract Non-obstructive azoospermia (NOA) severely affects male infertility, however, the deep mechanisms of this disease are rarely interpreted. In this study, we find that undifferentiated spermatogonial stem cells (SSCs) still exist in the basal compartment of the seminiferous tubules and the blood–testis barrier (BTB) formed by the interaction of neighbor Sertoli cells (SCs) is incomplete in NOA patients with spermatogenic maturation arrest. The adhesions between SCs and germ cells (GCs) are also broken in NOA patients. Meanwhile, the expression level of geranylgeranyl diphosphate synthase (Ggpps), a key enzyme in mevalonate metabolic pathway, is lower in NOA patients than that in obstructive azoospermia (OA) patients. After Ggpps deletion specifically in SCs, the mice are infertile and the phenotype of the SC-Ggpps−/− mice is similar to the NOA patients, where the BTB and the SC–GC adhesions are severely destroyed. Although SSCs are still found in the basal compartment of the seminiferous tubules, fewer mature spermatocyte and spermatid are found in SC-Ggpps−/− mice. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Further examination suggests that the defect is mediated by the aberrant protein isoprenylation of RhoA and Ras family after Ggpps deletion. The exciting finding is that when the knockout mice are injected with berberine, the abnormal cell adhesions are ameliorated and spermatogenesis is partially restored. Our data suggest that the reconstruction of disrupted BTB is an effective treatment strategy for NOA patients with spermatogenic maturation arrest and hypospermatogenesis. Introduction Mature SCs form three types of intercellular junctions: Spermatogenesis is a well-regulated and hierarchical cadherin-based adherens junctions, occludin-based tight process to ensure prolonged male reproductive cap- junctions, and connexin-based gap junctions. These junc- ability1,2. Sertoli cells (SCs) extend their thin cytoplasm tions are involved in forming the blood–testis barrier arms around all the germ cells (GCs) to nurture their (BTB)3. The BTB divides seminiferous epithelium into the development and these intercellular associations are basal and apical (adluminal) compartments, where the maintained throughout the process of spermatogenesis. different stages of spermatogenesis take place: the renewal and differentiation of spermatogonial stem cells (SSCs) and the preleptotene stage spermatocyte in the basal com- Correspondence: Haixiang Sun ([email protected]) or Bing Yao (yaobin@nju. partment, meiosis and spermiogenesis, and spermiation in edu.cn) or Chaojun Li ([email protected]) the adluminal compartment4. In addition to BTB, the 1MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and Jiangsu Key Laboratory of Molecular Medicine cell developing GCs also interact with SCs to form a number of biology, the Medical School of Nanjing University, Nanjing, China distinct stage-specific junctions5. Thus the integrity and 2 Collaborative Innovation Platform for Reproductive Biology and Technology architecture of the SCs are critical for the orderly pro- of the Medical School of Nanjing University, Nanjing, China 6,7 Full list of author information is available at the end of the article. gression of spermatogenesis . Edited by M. Agostini © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Zhu et al. Cell Death and Disease (2019) 10:450 Page 2 of 12 In varicocele patients, dysfunction of spermatogenesis dark–light cycles and free access to food and water. The may be associated with BTB disruption8. Non-obstructive experimental animal facility has been accredited by azoospermia (NOA) patients carried the WT1 mutant, and Association for Assessment and Accreditation of WT1 loss of function in mouse SCs led to BTB structural Laboratory Animal Care International (AAALAC) and all damage, which in turn resulted in GCs death9. According animal protocols used in this study were approved by the to previous report, undifferentiated spermatogonia was Institutional Animal Care and Use Committee (IACUC) able to survive when the BTB was disrupted, and they were of Model Animal Research Center of Nanjing University. sufficient to restore spermatogenesis theoretically10.An We collected 18 NOA patients and 5 OA patients, in vitro study also demonstrated that SSCs isolated from respectively, to perform immunofluorescence and obstructive azoospermia (OA) and NOA patients had high immunohistochemistry staining and seven NOA patients developmental capacity when supported with extracellular and three OA patients, respectively, to perform qRT-PCR. matrix (ECM) components11. These findings suggested the We obtained patient consent and approval beforehand for possibility that amelioration of disrupted BTB would the use of clinical samples, which were from Nanjing restore spermatogenesis in NOA patients. General Hospital and used for research purposes only. All Based on our previous study of patients with male the studies abide by the Declaration of Helsinki principles infertility who had been infected with the mumps virus before puberty, geranylgeranyl diphosphate synthase Mice and tissues (Ggpps)deficiency in the SCs could induce excessive We generated Sertoli cell-specific Ggpps deletion mice fl fl cytokine and chemokine synthesis, and result in the by crossing AMH-Cre transgenic mice16 with Ggpps / invasion of macrophage into seminiferous tubule during mice. No significant difference of fertility and weight were puberty when BTB was not completely formed. The observed among heterozygous and wild-type mice from macrophages in the seminiferous tubule would lead to the same litter. Therefore, we used the heterozygous as the developing GCs death when they penetrated into the controls in the present study. The reproductive capacity adluminal compartment and subsequently resulted in was determined by mating one male with three C57BL/6 infertility in adult mice12. GGPPS is a branch point females as previously published17. Genotyping was con- enzyme in the mevalonate pathway that catalyzes the ducted by using PCR (the primers for the PCR and the synthesis of GGPP from farnesyl diphosphate (FPP)13, qRT-PCR analyses are indicated in Table S1). The sperm which can prenylate signaling proteins such as Ras family. production was determined by dissecting epididymis in Herein, we demonstrate that deletion of Ggpps in the SCs 1X PBS, then incubating at 37 °C for 0.5 h and counting results in the destruction of the BTB and SC–GC adhe- the number of sperm under a microscope. The protocol sions through affecting the distribution of adhesion pro- for isolating primary SCs was performed as previously teins in seminiferous tubules. Studies in Drosophila stem reported18,19. Testis were fixed in 4% paraformaldehyde cells have shown that cadherins were indispensable for the and embedded in paraffin, sectioned (5 μm), and placed stem cell–niche interaction14 and the downregulation of on slides for immunofluorescence, immunohistochem- N-cadherin promoted germline stem cells (GSCs) differ- istry, and Tunel assay (Table 1). entiation by displacing GSCs away from the niche15, indicating that N-cadherin maintains the GSC pool. We Histology, immunofluorescence, Tunel assays, and biotin speculated that this kind of regulation may be involved in permeability assay maintaining the SSC pool in mammal. Hematoxylin & eosin (H&E) staining was performed on In this study, we demonstrate that the integrity of BTB is testis sections of the control and knockout mice as critical for spermatogenesis because the structure not only described previously20. For immunohistochemistry and seals the GCs from the immune system as previous report, immunofluorescence staining, paraffinsectionswerede- but also determines the distinct interactions between the paraffinized, rehydrated, and boiled in citrate buffer (pH SCs and the GCs at different developmental stages. We 6.0) to retrieve antigens. Then, paraffin sections and also explore the possibility that berberine could restore frozen sections were permeabilized, blocked, and incu- spermatogenesis via resealing the damaged BTB and pro- bated with the indicated primary antibodies at 4 °C pose that amelioration of disrupted
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