Wt1 gene encodes a nuclear transcription factor which is specifically expressed in ovarian granulosa cells and testicular Sertoli cells. Our previous studies demonstrated that Wt1 is required for the lineage specification of supporting cells and inactivation of Wt1 results in Sertoli cells to Leydig-like cells transformation. To test whether Wt1 is also involved in lineage maintenance of granulosa cells during ovary development, Wt1 was specifically deleted in pre-granulosa cells using Foxl2-cre. We found that the female Wt1−/flox; Foxl2-cre mice were infertile with atrophic ovaries and no growing follicles with multiple layers of granulosa cells were observed. A large number of 3β-HSD-positive steroidogenic cells were detected in ovaries of Wt1−/flox; Foxl2-cre mice during embryonic stage and these cells were derived from Foxl2-expressing pre-granulosa cells. The quantitative results showed the expression of granulosa cell marker genes (Foxl2, Follistatin) was downregulated and steroidogenic cell marker genes (3β-HSD, Cyp11a1, Star and Sf1) was dramatically increased in Wt1−/flox; Foxl2-cre ovaries. We also found that the meiosis of germ cells in Wt1−/flox; Foxl2-cre ovaries was delayed but not arrested. This study demonstrates that Wt1 is required for lineage maintenance of granulosa cells and inactivation of Wt1 results in pre-granulosa cells to steroidogenic cells transformation which in turn causes the defect of ovary development.
Coridius chinensis (C. chinensis) is a traditional Chinese medicine that has been used to treat pain, erectile dysfunction, and other diseases. Our previous study demonstrated that manganese‐induced reproductive damage was partially rescued by a medium dose of C. chinensis treatment in rat. However, the underlying mechanism is unknown. In this study, we found that the weight of reproductive organs and the sperm count in manganese‐exposed rat were partially rescued by C. chinensis extracts (CcE) treatment. The number of apoptotic cells was significantly decreased and the expression of malondialdehyde, cytochrome c, and caspase‐3 in manganese‐exposed rats was significantly decreased after high dose of CcE treatment. Further studies revealed that the activity of superoxide dismutase, total antioxidant capacity, and glutathione peroxidase enzymes was significantly increased in testis tissues and serum of manganese‐exposed rats with high dose of CcE treatment. Taken together, the results of this study suggest that CcE inhibits the Mn2+‐induced apoptosis in testes by inducing the activity of antioxidants.
Wilms’ tumour 1 (Wt1) encodes a zinc finger nuclear transcription factor which is mutated in 15–20% of Wilms’ tumor, a pediatric kidney tumor. Wt1 has been found to be involved in the development of many organs. In gonads, Wt1 is expressed in genital ridge somatic cells before sex determination, and its expression is maintained in Sertoli cells and granulosa cells after sex determination. It has been demonstrated that Wt1 is required for the survival of the genital ridge cells. Homozygous mutation of Wt1 causes gonad agenesis. Recent studies find that Wt1 plays important roles in lineage specification and maintenance of gonad somatic cells. In this review, we will summarize the recent research works about Wt1 in gonadal somatic cell differentiation.
Protein arginine methyltransferase 5 (Prmt5) is the major type II enzyme responsible for symmetric dimethylation of arginine. Here, we found PRMT5 was expressed at high level in ovarian granulosa cells of growing follicles. Inactivation of Prmt5 in granulosa cells resulted in aberrant follicle development and female infertility. In Prmt5-knockout mice, follicle development was arrested with disorganized granulosa cells in which WT1 expression was dramatically reduced and the expression of steroidogenesis-related genes was significantly increased. The premature differentiated granulosa cells were detached from oocytes and follicle structure was disrupted. Mechanism studies revealed that Wt1 expression was regulated by PRMT5 at the protein level. PRMT5 facilitated IRES-dependent translation of Wt1 mRNA by methylating HnRNPA1. Moreover, the upregulation of steroidogenic genes in Prmt5-deficient granulosa cells was repressed by Wt1 overexpression. These results demonstrate PRMT5 participates in granulosa cell lineage maintenance by inducing Wt1 expression. Our study uncovers a new role of post-translational arginine methylation in granulosa cell differentiation and follicle development.
FANCB protein is a major component of the Fanconi anemia (FA) core complex and plays important role in hematopoiesis and germ cell development. Deletion of Fancb gene causes the defect of primordial germ cells (PGCs) development and infertility in male mice. However, it remains unknown whether Fancb is required for female germ cell development. In this study, we found that the fertility of Fancb knockout male mice in C57/ICR mixed backgrounds was not affected. Female Fancb−/− mice were obtained by crossing Fancb+/− females with Fancb−/Y males. The number of PGCs was dramatically decreased in Fancb−/− females. Very few oocytes were observed after birth and primordial follicle pool was completely depleted at 6 weeks of age in Fancb−/− females. However, the remained oocytes from Fancb−/− mice were normal in fertilization and embryonic development from 2-cell to blastocyst stage. We also found that Fancb and Fancl double knockout males were also fertile and the number of sperm in epididymis was not reduced comparable to that of Fancb−/− and Fancl−/− single knockout mice. Taken together, these results demonstrated that Fancb is also essential for female germ cell development. Inactivation of Fancb causes massive germ cell loss and infertility in adult females. We also found that Fancb and Fancl do not act synergistically in regulating germ cell development.
Manganese (Mn 2+ ) is found in very small amounts in the body, but it plays an important role in maintaining normal physiological condition and involves in many cellular biological processes. It also involves the composition of many enzymes and affects the enzyme activity. It is also required for other aspects, such as blood glucose regulation, development of bone and reproduction, and brain (Aschner & Aschner, 2005;Greger, 1999). Although an adequate intake of Mn 2+ is necessary for the human body, the excessive Mn 2+ exposure can lead to male fertility decline. Numerous studies proved that environmental toxicants, manganese (Mohammed et al., 2018;
Although germ cell fate is believed to be determined by signaling factors from differentiated somatic cells, the molecular mechanism behind this process remains obscure. In this study, premature meiosis in male germ cells was observed during the embryonic stage by conditional activation of β‐catenin in Sertoli cells. Somatic and germ cell transcriptome results indicated that the BMP signaling pathway was enriched after β‐catenin activation. In addition, we observed a decreased DNA methylation within a reduction of DNMT3A in germ cells of β‐catenin activated testes and reversed increase after inhibiting BMP signaling pathway with LDN‐193189. We also found that Dazl expression was increased in β‐catenin activated testes and decreased after LDN treatment. Taken together, this study demonstrates that male germ cells entered meiosis prematurely during the embryonic stage after β‐catenin activated in Sertoli cells. BMP signaling pathway involved in germ cell meiosis initiation by mediating DNA methylation to induce meiotic genes expression.
Spermatogenesis is a highly coordinated process that initiates shortly after birth and continues throughout the lifespan of male animals. Foxo1 is a transcription factor and is involved in many biological processes. It has been reported that the inactivation of Foxo1 in gonocytes during the embryonic stage causes the defects of spermatogenesis. In the present study, we found that the inactivation of Foxo1 in spermatogonia after birth also caused germ cell loss and male infertility. We found that the initiation of meiosis was not affected; however, the germ cell development was arrested after meiosis and lack of mature spermatozoa in the cauda epididymis. We also found that the proliferation of Foxo1-deficient spermatogonia stem cells was significantly reduced under in vitro conditions. Further study revealed that inactivation of Pten in postnatal spermatogonia using Stra8-Cre did not affect germ cell development and the subcellular location of FOXO1 in Ptendeficient spermatogonia. This study demonstrated that Foxo1 was involved in the development of spermatogonia after birth and the function of Foxo1 was probably not regulated by PI3K/PTEN signaling.
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