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PubMed2006

DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages.

DNA methylation is necessary for the silencing of endogenous retrotransposons and the maintenance of monoallelic gene expression at imprinted loci and on the X chromosome. Dynamic changes in DNA methylation occur during the initial stages of primordial germ cell development; however, all consequences of this epigenetic reprogramming are not understood. DNA demethylation in postmigratory primordial germ cells coincides with erasure of genomic imprints and reactivation of the inactive X chromosome, as well as ongoing germ cell differentiation events. To investigate a possible role for DNA methylation changes in germ cell differentiation, we have studied several marker genes that initiate expression at this time. Here, we show that the postmigratory germ cell-specific genes Mvh, Dazl and Scp3 are demethylated in germ cells, but not in somatic cells. Premature loss of genomic methylation in Dnmt1 mutant embryos leads to early expression of these genes as well as GCNA1, a widely used germ cell marker. In addition, GCNA1 is ectopically expressed by somatic cells in Dnmt1 mutants. These results provide in vivo evidence that postmigratory germ cell-specific genes are silenced by DNA methylation in both premigratory germ cells and somatic cells. This is the first example of ectopic gene activation in Dnmt1 mutant mice and suggests that dynamic changes in DNA methylation regulate tissue-specific gene expression of a set of primordial germ cell-specific genes.

Animals↗
PubMed1990

A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo.

The murine oct-3 gene encodes a transcription factor containing a POU-specific domain and a homeodomain. In marked contrast to other homeodomain-encoding genes, oct-3 is expressed in the totipotent and pluripotent stem cells of the pregastrulation embryo and is down-regulated during differentiation to endoderm and mesoderm, suggesting that it has a role in early development. The oct-3 gene is also expressed in primordial germ cells and in the female germ line.

Amino Acid Sequence↗
PubMed1988

Placental alkaline phosphatase immunohistochemistry of intratubular malignant germ cells and associated testicular germ cell tumors.

Two hundred three testicular germ cell tumors were studied immunohistochemically for the presence of placental alkaline phosphatase (PLAP). Special emphasis was placed on the pattern and incidence of positive staining of intratubular malignant germ cells (ITMGCs) adjacent to tumors. 99% of cases with adjacent ITMGCs showed a positive staining reaction in some or all IT-MGCs present. Other germ cell elements showed at least a focal positive staining reaction in the following proportions: seminomas, 96%; embryonal carcinomas, 96%; yolk sac tumors, 25%; mature teratomas, 5%; immature teratomas, 4%; choriocarcinomas, 45%; and syncytiotrophoblasts, 43%. The staining pattern for seminomas tended to be diffuse, whereas for embryonal carcinomas the staining pattern was more focal. Yolk sac tumors stained inconsistently for PLAP and a positive reaction was limited to a small percentage of cells. Syncytiotrophoblasts, singly or in choriocarcinomas, also showed variable positivity. These results corroborate the fact that PLAP is a sensitive marker for ITMGC, seminoma, and embryonal carcinoma.

Adult↗
PubMed1994

Production of placental alkaline phosphatase (PLAP) and PLAP-like material by epithelial germ cell and non-germ cell tumours in vitro.

Placental and placental-like alkaline phosphatase (PLAP) levels in the culture media of 87 cell lines of neoplastic and 'normal' origin were measured by a conventional immunosorbent enzymatic assay (IAEA) and by a new immunoradiometric assay (IRMA). The IRMA detected immunoreactive PLAP in 37 of 80 (46%) human epithelial and germ cell cultures, while the IAEA detected PLAP in only 25 (33%). Of the 52 non-germ cell tumour cultures, the IRMA detected expression in 24 (46%) and the IAEA in only 16 (31%). In 17 cases (21%) the IRMA recorded levels double that of the IAEA, while in five cultures (6%) the reverse was true. The IRMA was much more robust than the IAEA and had considerably lower inter- and intra-assay coefficients of variation (3.75-8.5% vs 5.2-46%). Detection of PLAP(-like) expression by IAEA is dependent on neoplastic expression of enzymatically functional molecules and quantification assumes constant enzyme kinetics. PLAP-like material has a higher catalytic rate constant than PLAP and thus will give higher values on a stoichiometric basis in an IAEA. The higher detection rate and levels of PLAP-like material in neoplastic cultures when measured by the IRMA clearly demonstrate ectopic expression of non-enzymatic PLAP and PLAP-like genes. The incidence of PLAP(-like) expression by non-germ cell and possible germ cell tumours has been underestimated and its utility as a tumour marker should be re-examined using assays which measure antigen mass rather than phosphatase activity.

Alkaline Phosphatase↗
PubMed2005

The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours.

In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds. Ter is also a potent modifier of spontaneous testicular germ cell tumour (TGCT) susceptibility in the 129 family of inbred strains, and markedly increases TGCT incidence in 129-Ter/Ter males. In 129-Ter/Ter mice, some of the remaining PGCs transform into undifferentiated pluripotent embryonal carcinoma cells, and after birth differentiate into various cells and tissues that compose TGCTs. Here, we report the positional cloning of Ter, revealing a point mutation that introduces a termination codon in the mouse orthologue (Dnd1) of the zebrafish dead end (dnd) gene. PGC deficiency is corrected both with bacterial artificial chromosomes that contain Dnd1 and with a Dnd1-encoding transgene. Dnd1 is expressed in fetal gonads during the critical period when TGCTs originate. DND1 has an RNA recognition motif and is most similar to the apobec complementation factor, a component of the cytidine to uridine RNA-editing complex. These results suggest that Ter may adversely affect essential aspects of RNA biology during PGC development. DND1 is the first protein known to have an RNA recognition motif directly implicated as a heritable cause of spontaneous tumorigenesis. TGCT development in the 129-Ter mouse strain models paediatric TGCT in humans. This work will have important implications for our understanding of the genetic control of TGCT pathogenesis and PGC biology.

Alleles↗
PubMed1993

Developmental expression of alkaline phosphatase genes; reexpression in germ cell tumours and in vitro immortalized germ cells.

Human germ cell alkaline phosphatase (GCAP) is developmentally expressed in primordial germ cells and in trace amounts in the testis and thymus. The equivalent mouse isozyme, embryonic alkaline phosphatase (EAP), is similarly expressed in the testis and thymus but also from the 2-cell to blastocyst stage of preimplantation development. EAP has been found to be transiently expressed in M-phase spermatogenic cells in the mouse testis. These alkaline phosphatase isozymes serve as markers of germ cell differentiation and in the management of germ cell tumors. GCAP is expressed in carcinoma-in-situ and seminoma where serum GCAP levels are often elevated and may provide clinically useful information. However, GCAP is a polymorphic enzyme, and monoclonal antibodies to be used in the clinical evaluation of tumor tissues or fluids should be carefully evaluated for their ability to detect all allelic variants of GCAP.

Alkaline Phosphatase↗
PubMed1997

Porcine reproductive and respiratory syndrome virus replicates in testicular germ cells, alters spermatogenesis, and induces germ cell death by apoptosis.

Like other arteriviruses, porcine reproductive and respiratory syndrome virus (PRRSV) is shed in semen, a feature that is critical for the venereal transmission of this group of viruses. In spite of its epidemiological importance, little is known of the association of PRRSV or other arteriviruses with gonadal tissues. We experimentally infected a group of boars with PRRSV 12068-96, a virulent field strain. By combined use of in situ hybridization and immunohistochemistry, we detected infection by PRRSV in the testes of these boars. The PRRSV testicular replication in testis centers on two types of cells: (i) epithelial germ cells of the seminiferous tubules, primarily spermatids and spermatocytes, and (ii) macrophages, which are located in the interstitium of the testis. Histopathologically, hypospermatogenesis, formation of multinucleated giant cells (MGCs), and abundant germ cell depletion and death were observed. We obtained evidence that such germ cell death occurs by apoptosis, as determined by a characteristic histologic pattern and evidence of massive DNA fragmentation detected in situ (TUNEL [terminal deoxynucleotidyltransferase-mediated digoxigenin-UTP nick end labeling] assay). Simultaneously with these testicular alterations, we observed that there is a significant increase in the number of immature sperm cells (mainly MGCs, spermatids, and spermatocytes) in the ejaculates of the PRRSV-inoculated boars and that these cells are infected with PRRSV. Our results indicate that PRRSV may infect target cells other than macrophages, that these infected cells can be primarily responsible for the excretion of infectious PRRSV in semen, and that PRRSV induces apoptosis in these germ cells in vivo.

Animals↗
PubMed1998

Possible common origin of alpha-fetoprotein- and human chorionic gonadotropin--secreting cells in intracranial germ cell tumor. Case report.

A primary intracranial germ cell tumor in a 16-year-old boy secreted both alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). The tumor, located in the right thalamus, contained germinomatous, trophoblastic, and endodermal sinus components. To identify AFP- and HCG-secreting cells, germ cells from the surgical specimen were cultured in vitro. These cultured cells secreted AFP and HCG for 10 weeks, and immunohistochemical studies showed that some of the cells secreted both AFP and HCG. These findings suggest that multipotential germ cells migrate to the encephalic region and may become germ cell tumors containing various types of tissue.

Adolescent↗
PubMed1985

Frequency of intratubular germ cell neoplasia with invasive testicular germ cell tumors. Histologic and immunocytochemical features.

Intratubular germ cell neoplasia (ITGCN) has been regarded as the preinvasive stage of testicular germ cell tumors. We evaluated its frequency in 53 testicular germ cell tumors and determined whether immunohistochemical stains for alpha-fetoprotein, human chorionic gonadotropin, carcinoembryonic antigen, and ferritin demonstrated an advantage in its detection in comparison with hematoxylin-eosin and periodic acid-Schiff (PAS) stains. Residual seminiferous tubules were found at the periphery of the invasive neoplastic foci in 47 cases. Intratubular germ cell neoplasia was detected in several or multiple seminiferous tubules in 46 cases (98%). Exquisite localization of PAS-positive intracellular granules was present in all but one case of ITGCN. Focal immunocytochemical positivity for human chorionic gonadotropin, carcinoembryonic antigen, and ferritin was noted in 2.3% of cases. We conclude that ITGCN is present in most invasive germ cell tumors and the PAS stain is very reliable in its demonstration. Antigenic expression of the proteins that we examined is extremely limited in these primordial germ cells.

Carcinoembryonic Antigen↗
PubMed1989

Age-dependent Sertoli cell responsiveness to germ cells in vitro.

This study investigated the effect of germ cells (greater than 80% mid- and late-pachytene spermatocytes) on the secretion of androgen binding protein (ABP) and transferrin by monolayer cultures of Sertoli cells isolated from rats aged 10, 18 or 26 days. There was an age-dependent increase in secretion of ABP and transferrin. Treatment of the Sertoli cell monolayers with hypotonic buffer to remove residual germ cells reduced this increase significantly. On the other hand, addition of germ cells to hypotonic-treated Sertoli cell monolayers increased both basal and FSH + testosterone-stimulated ABP and transferrin secretion at all three ages, although Sertoli cells from 10-day-old animals showed the greatest response. Moreover, addition of germ cells reduced responsiveness to FSH + testosterone in Sertoli cell monolayers obtained from rats aged 18 or 26 days. In monolayers obtained from 10-day-old rats, the opposite effect was noted in the case of ABP secretion. The stimulatory effect of germ cells on ABP and transferrin secretion was proportional to their number, and was reversed 48 h after the germ cells added previously were removed by hypotonic treatment. Whereas the reversal was complete with cultures of Sertoli cells isolated from 18- and 26-day-old rats, approximately 40% of the stimulatory effect remained after removal of germ cells from cultures from the 10-day-old age group. Adhesion of germ cells to Sertoli cell monolayers was also found to be age-dependent, with the largest proportion of added germ cells adhering to Sertoli cells isolated at 18 and 26 days of age. It is concluded that germ cells can significantly and differentially modulate the basal and hormone-stimulated secretory activity of Sertoli cells in vitro and that Sertoli cell responsiveness to germ cells (pachytene spermatocytes) is age-dependent and seems to appear early during the maturation process, before these germ cells appear in the testis.

Aging↗
PubMed2001

Differentiation of mouse primordial germ cells into female or male germ cells.

Mouse primordial germ cells (PGCs) migrate from the base of the allantois to the genital ridge. They proliferate both during migration and after their arrival, until initiation of the sex-differentiation of fetal gonads. Then, PGCs enter into the prophase of the first meiotic division in the ovary to become oocytes, while those in the testis become mitotically arrested to become prospermatogonia. Growth regulation of mouse PGCs has been studied by culturing them on feeder cells. They show a limited period of proliferation in vitro and go into growth arrest, which is in good correlation with their developmental changes in vivo. However, in the presence of multiple growth signals, PGCs can restart rapid proliferation and transform into pluripotent embryonic germ (EG) cells. Observation of ectopic germ cells and studies of reaggregate cultures suggested that both male and female PGCs show cell-autonomous entry into meiosis and differentiation into oocytes if they were set apart from the male gonadal environments. Recently, we developed a two-dimensional dispersed culture system in which we can examine transition from the mitotic PGCs into the leptotene stage of the first meiotic division. Such entry into meiosis seems to be programmed in PGCs before reaching the genital ridges and unless it is inhibited by putative signals from the testicular somatic cells.

Animals↗
PubMed2003

Cadherin-mediated cell interaction regulates germ cell determination in mice.

The germ cell lineage segregates from the somatic cell lineages in early embryos. Germ cell determination in mice is not regulated by maternally inherited germplasm, but is initiated within the embryo during gastrulation. However, the mechanisms of germ cell specification in mice remain unknown. We located precursors to primordial germ cells (PGCs) within early embryos, and show here that cell-cell interaction among these precursors is required for germ cell specification. We found that the expression of a calcium-dependent cell adhesion molecule, E-cadherin, is restricted to the proximal region of extra-embryonic mesoderm that contains PGC precursors, and that blocking the functions of E-cadherin with an antibody inhibits PGC formation in vitro. These results showed that E-cadherin-mediated cell-cell interaction among cells containing PGC precursors is essential to directing such cells to the germ cell fate.

Animals↗
PubMed1990

Keratin 7 is a marker for a subset of trophoblastic cells in human germ cell tumors.

Human testicular germ cell tumors were studied immunohistochemically with the monoclonal antibody to the 54-kd keratin polypeptide (keratin 7) to determine whether this antibody could be used selectively to identify trophoblastic cells. The antibody reacted with the intermediate filaments in the cytoplasm of some cells in choriocarcinoma cell lines, and in trophoblastic cells in mixed germ cell tumors and a seminoma. It did not react with classic seminoma cells, embryonal carcinoma, yolk sac carcinoma, or somatic tissues of mixed germ cell tumors. On the basis of these data we conclude that monoclonal antibody to keratin 7 is a marker for a subset of trophoblastic cells in human germ cell tumors.

Adult↗
PubMedDate not supplied

Sertoli cells of intratubular germ cell neoplasia express beta 2 microglobulin.

The cells in intratubular germ cell neoplasia in the vicinity of 38 germ cell tumors of the testis, including 20 pure seminomas, were studied for the expression of beta 2-microglobulin (beta 2m), the constant component of all HLA class I molecules. Immunohistochemistry using antibodies towards beta 2m, vimentin, placental alkaline phosphatase, and ferritin was employed. Whereas the intratubular cells in normal testis are beta 2m negative, beta 2m positive cells were identified in intratubular germ cell neoplasia tubules in 55 per cent of all tumors and in 60 per cent of the seminomas. The tubules with beta 2m positive cells were located in areas with invasive tumor or in the vicinity of such areas. The beta 2m positive cells were identified as Sertoli cells by morphology and by their staining with anti-vimentin. Neoplastic germ cells, identified by morphology and staining with anti-placental alkaline phosphatase and anti-ferritin were beta 2-microglobulin negative. The most intensely beta 2m-stained Sertoli cells were found in tubules with high concentrations of neoplastic germ cells. Intensely stained Sertoli cells were also found in 'Sertoli cell only' tubules inside invasive tumors and in areas without lymphocytic infiltration. The cells in adjacent normal tubules were beta 2m negative.

Carcinoma↗
PubMed1990

Testicular tumours in infancy and childhood--a review of 10 germ cell tumours and 10 non germ cell tumours.

Between 1961 and 1989 twenty testicular tumours were treated at the Basel University Children's Hospital. Ten were non germ cell tumours (50%) and a further 10 (50%) were germ cell tumours. Of the germ cell tumours six were benign teratomas, two yolk sac tumours and a further two were teratocarcinomas. In the non germ cell group eight tumours originated from paratesticular structures, one of which was a malignant rhabdomyosarcoma. The remaining two neoplasms originated from the supporting testicular tissues. The clinical presentation, the protocol of treatment and the long-term outcome are discussed. We advocate local tumour excision in benign cases (proven by instant frozen section) if normal testicular tissue can be preserved. In malignant germ cell tumours primary orchiectomy and high spermatic cord ligation is the treatment of choice. Secondary chemotherapy and/or retroperitoneal lymph node dissection is only added if the tumour markers alpha-fetoprotein and beta-human chorionic gonadotropin remain present in high serum levels postoperatively. Rhabdomyosarcomas are treated by surgical excision, primary chemotherapy and radiotherapy. All of the five patients (25%) suffering from malignant testicular tumours survived. A long-term follow-up (mean 12 years) did not show any evidence of recurrent local or metastatic disease.

Adolescent↗
PubMed1987

Tests for urethane induction of germ-cell mutations and germ-cell killing in the mouse.

Urethane, a chemical that has given varied results in mutagenesis assays, was tested in the mouse specific-locus test, and its effect on germ-cell survival was explored. Altogether 32,828 offspring were observed from successive weekly matings of males exposed to the maximum tolerated i.p. dose of 1750 mg urethane/kg. The combined data rule out (at the 5% significance level) an induced mutation rate greater than 1.7 times the historical control rate. For spermatogonial stem cells alone, the multiple ruled out is 3.2, and for poststem-cell stages, 3.5. Litter sizes from successive conceptions made in any of the first 7 weeks give no indication of induced dominant lethality, confirming results of past dominant-lethal assays. That urethane (or an active metabolite) reaches germ cells is indicated by SCE induction in spermatogonia demonstrated by other investigators. Cytotoxic effects in spermatogonia are suggested by our finding of a slight reduction in numbers of certain types of spermatogonia in seminiferous tubule cross-sections and of a borderline decrease in the number of litters conceived during the 8th and 9th posttreatment weeks. The negative results for induction of gene mutations as well as clastogenic damage are at variance with Nomura's reports of dominant effects (F1 cancers and malformations) produced by urethane.

Animals↗
PubMed1986

Cell-cell interaction between rat Sertoli cells and mouse germ cells in vitro.

An antiserum against rat germ cell membranes was prepared, and after absorption with protein extracts of rat liver and kidney and mouse testis, this antiserum reacted only with rat germ cell membranes and juxtanuclear vesicles in rat Sertoli cells. Germ cell-free rat Sertoli cell monolayers were cultured in vitro. Freshly isolated mouse germ cells adhered to these monolayers within 1 h. After a minimum of 3 days of such a co-culture, immunofluorescence and immunoblotting revealed that the mouse germ cells had obtained rat-antigenic determinants in their membranes. Our results indicate that this appearance of rat-specific antigens on mouse germ cells is specific and inducible.

Animals↗