Regulation of meiotic entry and gonadal sex differentiation in the human: normal and disrupted signaling

2014 ◽  
Vol 5 (4) ◽  
pp. 331-341 ◽  
Author(s):  
Anne Jørgensen ◽  
Ewa Rajpert-De Meyts
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Fetal Development ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Sex Differentiation ◽  
Cell Cancer ◽  
Testicular Germ Cell ◽  
Unique Type ◽  
Germ Cell Differentiation

AbstractMeiosis is a unique type of cell division that is performed only by germ cells to form haploid gametes. The switch from mitosis to meiosis exhibits a distinct sex-specific difference in timing, with female germ cells entering meiosis during fetal development and male germ cells at puberty when spermatogenesis is initiated. During early fetal development, bipotential primordial germ cells migrate to the forming gonad where they remain sexually indifferent until the sex-specific differentiation of germ cells is initiated by cues from the somatic cells. This irreversible step in gonadal sex differentiation involves the initiation of meiosis in fetal ovaries and prevention of meiosis in the germ cells of fetal testes. During the last decade, major advances in the understanding of meiosis regulation have been accomplished, with the discovery of retinoic acid as an inducer of meiosis being the most prominent finding. Knowledge about the molecular mechanisms regulating meiosis signaling has mainly been established by studies in rodents, while this has not yet been extensively investigated in humans. In this review, the current knowledge about the regulation of meiosis signaling is summarized and placed in the context of fetal gonad development and germ cell differentiation, with emphasis on results obtained in humans. Furthermore, the consequences of dysregulated meiosis signaling in humans are briefly discussed in the context of selected pathologies, including testicular germ cell cancer and some forms of male infertility.

scholarly journals Ectopic FGF23 production induces mineral changes, osteogenic transdifferentiation, and cancer associated microcalcifications

2020 ◽  
Author(s):  
Ida Marie Boisen ◽  
John Erik Nielsen ◽  
Ireen Kooij ◽  
Jovana Kaludjerovic ◽  
Peter J. O’Shaughnessy ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Germ Cell ◽  
Phosphatase Activity ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Alkaline Phosphatase Activity ◽  
Cell Cancer ◽  
Seminiferous Tubules ◽  
Testicular Germ Cell ◽  
Increased Risk

AbstractTesticular microcalcifications consist of hydroxyapatite and their demonstration by ultrasound has been associated with increased risk of testicular germ cell cancer (TGCT). Here, we show that fibroblast growth factor 23 (FGF23), a bone-specific regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and thus rapidly cleaved into a C-terminal fragment that serves as a competitive antagonist for full-length FGF23. High levels of C-terminal FGF23 occupy the receptor formed by Klotho and FGF receptor 1 (FGFR1) in the germ cells facilitating a shift in the expression of phosphate transport proteins from SLC34A2 to SLC34A1 in seminiferous tubules adjacent to GCNIS. Fgf23 knockout mice have a marked epididymal deposition of hydroxyapatite, while the testicular phenotype is milder with spermatogenic arrest and focal germ-cell-specific expression of the bone-like markers runt-related transcription factor 2 (RUNX2) and bone gamma-carboxyglutamic acid-containing protein (BGLAP). In accordance, mice with no functional androgen receptor and lack of circulating gonadotropins develop microcalcifications in 94% of cases and have lower Slc34a2, and higher Slc34a1 and Bglap expression. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2, and focally germ cells express SLC34A1, BGLAP, and RUNX2. Importantly, calcium or phosphate induced osteogenic transdifferentiation of a spermatogonial cell line in vitro demonstrated by induction of alkaline phosphatase activity and deposition of hydroxyapatite, which could be fully rescued by pyrophosphate (PPi). Severe microcalcifications were also found in a mouse model with Sertoli-cell ablation particularly when Sertoli-ablation was conducted prepubertally where the germ cells retain stem cell potential. In conclusion, cancer-related microcalcifications may arise secondary to gonadal mineral alterations, which in combination with impaired Sertoli cell function and reduced PPi due to high alkaline phosphatase activity in GCNIS and TGCTs, facilitates osteogenic transdifferentiation of testicular germ cells and deposition of hydroxyapatite.

scholarly journals Environmental exposures, fetal testis development and function: phthalates and beyond

Reproduction ◽  
2021 ◽  
Author(s):  
Hui Li ◽  
Daniel J. Spade
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Current Knowledge ◽  
Environmental Chemicals ◽  
Environmental Toxicants ◽  
Cell Contacts ◽  
Testis Development ◽  
Fetal Testis

Fetal development of the mammalian testis relies on a series of interrelated cellular processes: commitment of somatic progenitor cells to Sertoli and Leydig cell fate, migration of endothelial cells and Sertoli cells, differentiation of germ cells, deposition of basement membrane, and establishment of cell-cell contacts, including Sertoli-Sertoli and Sertoli-germ cell contacts. These processes are orchestrated by intracellular, endocrine, and paracrine signaling processes. Because of this complexity, testis development can be disrupted by a variety of environmental toxicants. Toxicity of phthalic acid esters (phthalates) to the fetal testis has been the subject of extensive research for two decades, and phthalates have become an archetypal fetal testis toxicant. Phthalates disrupt the seminiferous cord formation and maturation, Sertoli cell function, biosynthesis of testosterone in Leydig cells, and impair germ cell survival and development, producing characteristic multinucleated germ cells. However, the mechanisms responsible for these effects are not fully understood. This review describes current knowledge of the adverse effects of phthalates on the fetal testis and their associated windows of sensitivity, and compares and contrasts the mechanisms by which toxicants of current interest, bisphenol A and its replacements, analgesics, and perfluorinated alkyl substances, alter testicular developmental processes. Working towards a better understanding of the molecular mechanisms responsible for phthalate toxicity will be critical for understanding the long-term impacts of environmental chemicals and pharmaceuticals on human reproductive health.

scholarly journals Crosstalk Between Retinoic Acid and Sex-Related Genes Controls Germ Cell Fate and Gametogenesis in Medaka

2021 ◽  
Vol 8 ◽  
Author(s):  
Mateus C. Adolfi ◽  
Amaury Herpin ◽  
Anabel Martinez-Bengochea ◽  
Susanne Kneitz ◽  
Martina Regensburger ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
Sex Determination ◽  
Germ Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Sex Differentiation ◽  
Model Species ◽  
Fish Model ◽  
Germ Cell Differentiation

Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of Stra8. In this study, we used a fish model species for sex determination and lacking the stra8 gene, the Japanese medaka (Oryzias latipes), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of dmrt1a and amh. Disruption of the RA degrading enzyme gene cyp26a1 induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of cyp26a1–/–adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a stra8 independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes.

437: Predictability of Androgen Deficiency in Testicular Germ Cell Cancer Patients by Residual Testicular Volume

2005 ◽  
Vol 173 (4S) ◽  
pp. 119-119 ◽  
Author(s):  
Gerald Puehse ◽  
Armin Secker ◽  
Sebastian Kemper ◽  
Lothar Hertle ◽  
Sabine Kliesch
Keyword(s):  
Germ Cell ◽  
Cancer Patients ◽  
Cell Cancer ◽  
Germ Cell Cancer ◽  
Testicular Volume ◽  
Androgen Deficiency ◽  
Testicular Germ Cell ◽  
Testicular Germ Cell Cancer

Acid isoelectric variants of hCG in testicular germ cell cancer

1984 ◽  
Vol 104 (4_Supplb) ◽  
pp. S122
Author(s):  
K. MANN ◽  
G. SPÖTTL ◽  
B. PUTZ ◽  
H. J. KARL
Keyword(s):  
Germ Cell ◽  
Cell Cancer ◽  
Germ Cell Cancer ◽  
Testicular Germ Cell ◽  
Testicular Germ Cell Cancer

Molecular Mechanisms of Resistance in Testicular Germ Cell Tumors - clinical Implications

2018 ◽  
Vol 18 (10) ◽  
pp. 967-978 ◽  
Author(s):  
Katarina Kalavska ◽  
Vincenza Conteduca ◽  
Ugo De Giorgi ◽  
Michal Mego
Keyword(s):  
Germ Cell ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Apoptotic Cell ◽  
Germ Cell Tumors ◽  
Treatment Resistance ◽  
Experimental Models ◽  
Testicular Germ Cell Tumors ◽  
Testicular Germ Cell ◽  
Repair Capacity

Testicular germ cell tumors (TGCTs) represent the most common malignancy in men aged 15-35. Due to these tumors’ biological and clinical characteristics, they can serve as an appropriate system for studying molecular mechanisms associated with cisplatin-based treatment resistance. This review describes treatment resistance from clinical and molecular viewpoints. Cisplatin resistance is determined by various biological mechanisms, including the modulation of the DNA repair capacity of cancer cells, alterations to apoptotic cell death pathways, deregulation of gene expression pathways, epigenetic alterations and insufficient DNA binding. Moreover, this review describes TGCTs as a model system that enables the study of the cellular features of cancer stem cells in metastatic process and describes experimental models that can be used to study treatment resistance in TGCTs. All of the abovementioned aspects may help to elucidate the molecular mechanisms underlying cisplatin resistance and may help to identify promising new therapeutic targets.

scholarly journals Müllerian Inhibiting Substance Is Required for Germ Cell Proliferation during Early Gonadal Differentiation in Medaka (Oryzias latipes)

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1813-1819 ◽  
Author(s):  
Eri Shiraishi ◽  
Norifumi Yoshinaga ◽  
Takeshi Miura ◽  
Hayato Yokoi ◽  
Yuko Wakamatsu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Germ Cells ◽  
Sex Differentiation ◽  
Somatic Cells ◽  
Oryzias Latipes ◽  
Cell Number ◽  
Gonadal Differentiation ◽  
Loss Of Function ◽  
Germ Cell Proliferation

Müllerian inhibiting substance (MIS) is a glycoprotein belonging to the TGF-β superfamily. In mammals, MIS is responsible for the regression of Müllerian ducts in the male fetus. However, the role of MIS in gonadal sex differentiation of teleost fish, which have no Müllerian ducts, has yet to be clarified. In the present study, we examined the expression pattern of mis and mis type 2 receptor (misr2) mRNAs and the function of MIS signaling in early gonadal differentiation in medaka (teleost, Oryzias latipes). In situ hybridization showed that both mis and misr2 mRNAs were expressed in the somatic cells surrounding the germ cells of both sexes during early sex differentiation. Loss-of-function of either MIS or MIS type II receptor (MISRII) in medaka resulted in suppression of germ cell proliferation during sex differentiation. These results were supported by cell proliferation assay using 5-bromo-2′-deoxyuridine labeling analysis. Treatment of tissue fragments containing germ cells with recombinant eel MIS significantly induced germ cell proliferation in both sexes compared with the untreated control. On the other hand, culture of tissue fragments from the MIS- or MISRII-defective embryos inhibited proliferation of germ cells in both sexes. Moreover, treatment with recombinant eel MIS in the MIS-defective embryos dose-dependently increased germ cell number in both sexes, whereas in the MISRII-defective embryos, it did not permit proliferation of germ cells. These results suggest that in medaka, MIS indirectly stimulates germ cell proliferation through MISRII, expressed in the somatic cells immediately after they reach the gonadal primordium.

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