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Free access

Wan-Sheng Liu, Yaqi Zhao, Chen Lu, Gang Ning, Yun Ma, Francisco Diaz, and Michael O'Connor

Preferentially expressed antigen in melanoma (PRAME) is a cancer/testis antigen that is predominantly expressed in normal testicular tissues and a variety of tumors. The function of the PRAME family in spermatogenesis remains unknown. This study was designed to characterize the Y-linked PRAME (PRAMEY) protein during spermatogenesis in cattle. We found that PRAMEY is a novel male germ cell-specific, and a germinal granule-associated protein that is expressed in spermatogenic cells during spermatogenesis. The intact PRAMEY protein (58 kDa) was detected in different ages of testes but not in epididymal spermatozoa. A PRAMEY isoform (30 kDa) was highly expressed only in testes after puberty and in epididymal spermatozoa. This isoform interacts with PP1γ2 and is likely the mature protein present in the testes and sperm. Immunofluorescent staining demonstrated that PRAMEY was located predominantly in the acrosome granule of spermatids, and in acrosome and flagellum of spermatozoa. Immunogold electron microscopy further localized the PRAMEY protein complex to the nucleus and several cytoplasmic organelles, including the rough endoplasmic reticulum, some small vesicles, the intermitochondrial cement, the chromatoid body and the centrioles, in spermatogonia, spermatocytes, spermatids and/or spermatozoa. PRAMEY was highly enriched in and structurally associated with the matrix of the acrosomal granule (AG) in round spermatids, and migrated with the expansion of the AG during acrosomal biogenesis. While the function of PRAMEY remains unclear during spermatogenesis, our results suggest that PRAMEY may play an essential role in acrosome biogenesis and spermatogenesis.

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Open access

Lin Chen, Weijie Zhao, Mengxiong Li, Yazhu Yang, Chengzi Tian, Dengyang Zhang, Zhiguang Chang, Yunzhe Zhang, Zhizhuang Joe Zhao, Yun Chen, and Lin Ma

Decidualization is the process of conversion of endometrial stromal cells (ESCs) into decidual stromal cells (DSCs), which is caused by progesterone production that begins during the luteal phase of the menstrual cycle and then increases throughout pregnancy dedicated to support embryonic development. Decidualization deficiency is closely associated with various pregnancy complications, such as recurrent miscarriage (RM). Here, we reported that Src-homology-2-containing phospho-tyrosine phosphatase (SHP2), a key regulator in the signal transduction process downstream of various receptors, plays an indispensable role in decidualization. SHP2 expression was upregulated during decidualization. SHP2 inhibitor RMC-4550 and shRNA mediated SHP2 reduction resulted in a decreased level of phosphorylation of ERK and aberrant cytoplasmic localization of progesterone receptor (PR), coinciding with reduced expression of IGFBP1 and various other target genes of decidualization. Solely inhibiting ERK activity recapitulated these observations. Administration of RMC-4550 led to decidualization deficiency and embryo absorption in mouse. Moreover, reduced expression of SHP2 was detected in decidua of RM patients. Our results revealed that SHP2 is key to PR's nuclear localization, thereby indispensable for decidualization and that reduced expression of SHP2 might be engaged in the pathogenesis of RM.

Free access

Jing Tong, Shile Sheng, Yun Sun, Huihui Li, Wei-Ping Li, Cong Zhang, and Zi-Jiang Chen

Good-quality oocytes are critical for the success of in vitro fertilization (IVF), but, to date, there is no marker of ovarian reserve available that can accurately predict oocyte quality. Melatonin exerts its antioxidant actions as a strong radical scavenger that might affect oocyte quality directly as it is the most potent antioxidant in follicular fluid. To investigate the precise role of endogenous melatonin in IVF outcomes, we recruited 61 women undergoing treatment cycles of IVF or intracytoplasmic sperm injection (ICSI) procedures and classified them into three groups according to their response to ovarian stimulation. Follicular fluid was collected to assess melatonin levels using a direct RIA method. We found good correlations between melatonin levels in follicular fluid with age, anti-Müllerian hormone (AMH) and baseline follicle-stimulating hormone (bFSH), all of which have been used to predict ovarian reserve. Furthermore, as melatonin levels correlated to IVF outcomes, higher numbers of oocytes were collected from patients with higher melatonin levels and consequently the number of oocytes fertilized, zygotes cleaved, top quality embryos on D3, blastocysts obtained and embryos suitable for transplantation was higher. The blastocyst rate increased in concert with the melatonin levels across the gradient between the poor response group and the high response group. These results demonstrated that the melatonin levels in follicular fluid is associated with both the quantity and quality of oocytes and can predict IVF outcomes as well making them highly relevant biochemical markers of ovarian reserve.

Free access

Jingmei Hou, Shi Yang, Hao Yang, Yang Liu, Yun Liu, Yanan Hai, Zheng Chen, Ying Guo, Yuehua Gong, Wei-Qiang Gao, Zheng Li, and Zuping He

Infertility is a major and largely incurable disease caused by disruption and loss of germ cells. It affects 10–15% of couples, and male factor accounts for half of the cases. To obtain human male germ cells ‘especially functional spermatids’ is essential for treating male infertility. Currently, much progress has been made on generating male germ cells, including spermatogonia, spermatocytes, and spermatids, from various types of stem cells. These germ cells can also be used in investigation of the pathology of male infertility. In this review, we focused on advances on obtaining male differentiated germ cells from different kinds of stem cells, with an emphasis on the embryonic stem (ES) cells, the induced pluripotent stem (iPS) cells, and spermatogonial stem cells (SSCs). We illustrated the generation of male differentiated germ cells from ES cells, iPS cells and SSCs, and we summarized the phenotype for these stem cells, spermatocytes and spermatids. Moreover, we address the differentiation potentials of ES cells, iPS cells and SSCs. We also highlight the advantages, disadvantages and concerns on derivation of the differentiated male germ cells from several types of stem cells. The ability of generating mature and functional male gametes from stem cells could enable us to understand the precise etiology of male infertility and offer an invaluable source of autologous male gametes for treating male infertility of azoospermia patients.

Free access

Chencheng Yao, Yun Liu, Min Sun, Minghui Niu, Qingqing Yuan, Yanan Hai, Ying Guo, Zheng Chen, Jingmei Hou, Yang Liu, and Zuping He

Spermatogenesis is composed of three distinctive phases, which include self-renewal of spermatogonia via mitosis, spermatocytes undergoing meiosis I/II and post-meiotic development of haploid spermatids via spermiogenesis. Spermatogenesis also involves condensation of chromatin in the spermatid head before transformation of spermatids to spermatozoa. Epigenetic regulation refers to changes of heritably cellular and physiological traits not caused by modifications in the DNA sequences of the chromatin such as mutations. Major advances have been made in the epigenetic regulation of spermatogenesis. In this review, we address the roles and mechanisms of epigenetic regulators, with a focus on the role of microRNAs and DNA methylation during mitosis, meiosis and spermiogenesis. We also highlight issues that deserve attention for further investigation on the epigenetic regulation of spermatogenesis. More importantly, a thorough understanding of the epigenetic regulation in spermatogenesis will provide insightful information into the etiology of some unexplained infertility, offering new approaches for the treatment of male infertility.

Free access

Yun-Kao Cao, Zhi-Sheng Zhong, Da-Yuan Chen, Gui-Xue Zhang, Heide Schatten, and Qing-Yuan Sun

The small GTPase Ran controls numerous cellular processes of the mitotic cell cycle. In this experiment, we investigated the localization and possible roles of Ran during mouse oocyte meiotic maturation, fertilization and early cleavage by using confocal laser scanning microscopy, antibody microinjection and microtubule disturbance. The results showed that Ran was localized mainly in the nucleus (except for the nucleolus) in the oocyte, zygote and early embryo. At pro-metaphase of meiosis I, Ran distributed throughout the cell, but predominantly concentrated around the condensed chromosomes. During the completion of meiosis I and meiosis II, it concentrated to the meiotic spindle microtubules except for the midbody region. After sperm penetration, Ran dispersed with the extrusion of the second polar body and gradually concentrated in the male and female pronuclei thereafter. Ran was also observed to exist diffusely in the cytoplasm in prophase; it concentrated at the mitotic spindle, and migrated to the nucleus during early cleavage. Ran’s concentration around the spindle disappeared when microtubule assembly was inhibited by colchicine, while it was concentrated around the chromosomes after microtubule stabilization with taxol treatment. Ran did not display any role in cytokinesis during division when pseudo-cleavage of germinal vesicle-intact oocytes was induced. Anti-Ran antibody microinjection decreased the germinal vesicle breakdown and the first polar body extrusion, and distorted spindle organization and chromosome alignment. Our results indicate that Ran has a cell cycle-dependent localization and may have regulatory roles in cell cycle progression and microtubule organization in mouse oocytes, fertilized eggs and early embryos.

Free access

Ma Tian-Zhong, Chen Bi, Zhang Ying, Jing Xia, Peng Cai-Ling, Zhang Yun-Shan, Huang Mei-Wen, and Niu Yan-Ru


Emx2 deletion impairs the growth and maintenance of the genital ridge. However, its role in subsequent germ cell differentiation during embryonic stages is unknown. Using a tamoxifen-inducible Cre-loxP mouse model (Emx2 flox/flox, Cre-ER TM, hereafter called as Emx2 knockdown), we showed that germ cell differentiation was impaired in Emx2-knockdown testes. Representative characteristics of male germ cell differentiation, including a reduced ability to form embryonic germ (EG) cell colonies in vitro, down-regulation of pluripotency markers and G1/G0 arrest, did not occur in Emx2-knockdown testes. Furthermore, FGF9 and NODAL signalling occurred at abnormally high levels in Emx2-knockdown testes. Both blocking FGF9 signalling with SU5402 and inhibiting NODAL signalling with SB431542 allowed germ cells from Emx2-knockdown testes to differentiate in vitro. Therefore, EMX2 in somatic cells is required to trigger germ cell differentiation in XY foetuses, posterior to its previously reported role in the growth and maintenance of the genital ridge.

Free access

Rui-Song Ye, Meng Li, Chao-Yun Li, Qi-En Qi, Ting Chen, Xiao Cheng, Song-Bo Wang, Gang Shu, Li-Na Wang, Xiao-Tong Zhu, Qing-Yan Jiang, Qian-Yun Xi, and Yong-Liang Zhang

FSH plays an essential role in processes involved in human reproduction, including spermatogenesis and the ovarian cycle. While the transcriptional regulatory mechanisms underlying its synthesis and secretion have been extensively studied, little is known about its posttranscriptional regulation. A bioinformatics analysis from our group indicated that a microRNA (miRNA; miR-361-3p) could regulate FSH secretion by potentially targeting the FSHB subunit. Herein, we sought to confirm these findings by investigating the miR-361-3p-mediated regulation of FSH production in primary pig anterior pituitary cells. Gonadotropin-releasing hormone (GnRH) treatment resulted in an increase in FSHB synthesis at both the mRNA, protein/hormone level, along with a significant decrease in miR-361-3p and its precursor (pre-miR-361) levels in time- and dose-dependent manner. Using the Dual-Luciferase Assay, we confirmed that miR-361-3p directly targets FSHB. Additionally, overexpression of miR-361-3p using mimics significantly decreased the FSHB production at both the mRNA and protein levels, with a reduction in both protein synthesis and secretion. Conversely, both synthesis and secretion were significantly increased following miR-361-3p blockade. To confirm that miR-361-3p targets FSHB, we designed FSH-targeted siRNAs, and co-transfected anterior pituitary cells with both the siRNA and miR-361-3p inhibitors. Our results indicated that the siRNA blocked the miR-361-3p inhibitor-mediated upregulation of FSH, while no significant effect on non-target expression. Taken together, our results demonstrate that miR-361-3p negatively regulates FSH synthesis and secretion by targeting FSHB, which provides more functional evidence that a miRNA is involved in the direct regulation of FSH.