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PubMed1995

DNA content and expression of tumour markers in germ cells adjacent to germ cell tumours in childhood: probably a different origin for infantile and adolescent germ cell tumours.

The origin of testicular germ cell tumours occurring during childhood is poorly understood. In adults, the classical seminomas and non-seminomas originate from carcinoma in situ of the testis, which can usually also be detected in seminiferous tubules adjacent to the tumours. In order to contribute with information regarding a possible association between carcinoma in situ and the childhood group of germ cell tumours, we investigated seminiferous tubules adjacent to 13 infantile yolk sac tumours, five infantile teratomas, and six adolescent germ cell tumours of various types, using morphological evaluation, immunohistochemical staining with markers for carcinoma in situ cells, and densitometric DNA measurement of the germ cells. We detected clear differences between the germ cell populations adjacent to adolescent and infantile germ cell tumours. The former were associated with both normal germ cells and carcinoma in situ cells, like germ cell tumours occurring in adult men. Although we were in doubt in two cases, the infantile cell germ cell tumours were in general not associated with carcinoma in situ cells. The aetiology of infantile yolk sac tumours and teratomas may therefore be fundamentally different from that of adolescent and adult germ cell tumours. The origin of yolk sac tumours and teratomas remains to be elucidated.

Adolescent↗
PubMed2002

Signaling from germ cells mediated by the rhomboid homolog stet organizes encapsulation by somatic support cells.

Germ cells normally differentiate in the context of encapsulating somatic cells. However, the mechanisms that set up the special relationship between germ cells and somatic support cells and the signals that mediate the crucial communications between the two cell types are poorly understood. We show that interactions between germ cells and somatic support cells in Drosophila depend on wild-type function of the stet gene. In males, stet acts in germ cells to allow their encapsulation by somatic cyst cells and is required for germ cell differentiation. In females, stet function allows inner sheath cells to enclose early germ cells correctly at the tip of the germarium. stet encodes a homolog of rhomboid, a component of the epidermal growth factor receptor signaling pathway involved in ligand activation in the signaling cell. The stet mutant phenotype suggests that stet facilitates signaling from germ cells to the epidermal growth factor receptor on somatic cells, resulting in the encapsulation of germ cells by somatic support cells. The micro-environment provided by the surrounding somatic cells may, in turn, regulate differentiation of the germ cells they enclose.

Animals↗
PubMed2006

Gender differences in the induction of chromosomal aberrations and gene mutations in rodent germ cells.

Germ cell mutagenicity testing provides experimental data to quantify genetic risk for exposed human populations. The majority of tests are performed with exposure of males, and female data are relatively rare. The reason for this paucity lies in the differences between male and female germ cell biology. Male germ cells are produced throughout reproductive life and all developmental stages can be ascertained by appropriate breeding schemes. In contrast, the female germ cell pool is limited, meiosis begins during embryogenesis and oocytes are arrested over long periods of time until maturation processes start for small numbers of oocytes during the oestrus cycle in mature females. The literature data are reviewed to point out possible gender differences of germ cells to exogenous agents such as chemicals or ionizing radiation. From the limited information, it can be concluded that male germ cells are more sensitive than female germ cells to the induction of chromosomal aberrations and gene mutations. However, exceptions are described which shed doubt on the extrapolation of experimental data from male rodents to the genetic risk of the human population. Furthermore, the female genome may be more sensitive to mutation induction during peri-conceptional stages compared to the male genome of the zygote. With few exceptions, germ cell experiments have been carried out under high acute exposure to optimize the effects and to compensate for the limited sample size in animal experiments. Human exposure to environmental agents, on the other hand, is usually chronic and involves low doses. Under these conditions, gender differences may become apparent that have not been studied so far. Additionally, data are reviewed that suggest a false impression of safety when responses are negative under high acute exposure of male rodents while a mutational response is induced by low chronic exposure. The classical (morphological) germ cell mutation tests are not performed anymore because they are animal and time consuming. Nevertheless, information is needed to place genetic risk extrapolations on more solid grounds and thereby to prevent an increased genetic burden to future generations. It is pointed out that modern molecular methodologies are available now to experimentally address the open questions.

Animals↗
PubMed2006

Influence of sex chromosome constitution on the genomic imprinting of germ cells.

Germ cells in XY male mice establish site-specific methylation on imprinted genes during spermatogenesis, whereas germ cells in XX females establish their imprints in growing oocytes. We showed previously that in vitro, sex-specific methylation patterns of pluripotent stem cell lines derived from germ cells were influenced more by the sex chromosome constitution of the cells themselves than by the gender of the embryo from which they had been derived. To see whether the same situation would prevail in vivo, we have now determined the methylation status of H19 expressed from the maternal allele, and the expression and methylation status of a paternally expressed gene Peg3, in germ cells from sex-reversed and control embryos. For these imprinted genes, we conclude that the female imprint is a response of the germ cells to undergoing oogenesis, rather than to their XX chromosome constitution. Similarly, both our XY and our sex-reversed XX male germ cells clearly showed a male rather than a female pattern of DNA methylation; here, however, the sex chromosome constitution had a significant effect, with XX male germ cells less methylated than the XY controls.

Animals↗
PubMed2002

A germline-specific gap junction protein required for survival of differentiating early germ cells.

Germ cells require intimate associations and signals from the surrounding somatic cells throughout gametogenesis. The zero population growth (zpg) locus of Drosophila encodes a germline-specific gap junction protein, Innexin 4, that is required for survival of differentiating early germ cells during gametogenesis in both sexes. Animals with a null mutation in zpg are viable but sterile and have tiny gonads. Adult zpg-null gonads contain small numbers of early germ cells, resembling stem cells or early spermatogonia or oogonia, but lack later stages of germ cell differentiation. In the male, Zpg protein localizes to the surface of spermatogonia, primarily on the sides adjacent to the somatic cyst cells. In the female, Zpg protein localizes to germ cell surfaces, both those adjacent to surrounding somatic cells and those adjacent to other germ cells. We propose that Zpg-containing gap junctional hemichannels in the germ cell plasma membrane may connect with hemichannels made of other innexin isoforms on adjacent somatic cells. Gap junctional intercellular communication via these channels may mediate passage of crucial small molecules or signals between germline and somatic support cells required for survival and differentiation of early germ cells in both sexes.

Amino Acid Sequence↗
PubMed2003

Conservation of a Pumilio-Nanos complex from Drosophila germ plasm to human germ cells.

Germ cells are the cells which ultimately give rise to mature sperm and eggs. In model organisms such as flies and worms, several genes that are required for formation and maintenance of germ cells have been identified and their interactions are rapidly being delineated. By contrast, little is known of the genes required for development of human germ cells and it is not clear whether findings from model organisms will translate into knowledge of human germ cell development, especially given observations that reproductive pathways may evolve more rapidly than somatic pathways. The Pumilio and Nanos genes have been especially well-characterized in model organisms and encode proteins that interact and are required for development of germ stem cells in one or both sexes. Here we report the first characterization of a mammalian Nanos homolog, human NANOS1 ( NOS1). We show that human NOS1 protein interacts with the human PUMILIO-2 (PUM2) protein via highly conserved domains to form a stable complex. We also show that in men, the NOS1 and PUM2 proteins are particularly abundant in germline stem cells. These observations mirror those in distant species and document for the first time a conserved protein-protein interaction in germ cells from flies to humans. These results suggest the possibility that the interaction of PUM2 and NOS1 may play a conserved role in germ cell development and maintenance in humans as in model organisms.

Animals↗
PubMed2004

[Relationship between the Sertoli cell and germ cell apoptosis].

Germ cells exist in an environment created by Sertoli cells. The differentiation of germ cells from spermatogonia to sperm in the seminiferous epithelium is controlled by many factors such as hormones, growth factors, temperature and interaction with Sertoli cells. Paracrine signaling between these intimately associated cells also regulates the process of germ cell death. Sertoli cells' products play an important role in the process of germ cell differentiation in the testis, in which both the spontaneous and induced germ cell apoptosis often occur.

Animals↗
PubMed1983

In vitro culture of mouse primordial germ cells.

Germ cells were isolated from mouse fetal gonads 11 1/2-16 1/2 days post coitum (dpc), and exposed to various methods of in vitro culture. From 13 1/2 dpc onwards, both male and female germ cells survived well at 37 degrees C for several days. During the culture period the proportion of female germ cells in meiosis increased and later stages of meiotic prophase were seen. The gonadal environment is therefore not essential for the progress of meiosis. Male germ cells in vitro did not enter meiosis. Germ cells isolated from gonads 11 1/2 or 12 1/2 dpc did not survive at 37 degrees C in any of the three culture systems used (Petri dishes, microtest plate wells, drops under oil); cell density, substrate and culture medium were varied, and several additives tested, but no improvement in viability was detected. Below 30 degrees C, on the other hand, 11 1/2 and 12 1/2 day germ cells survived in vitro for at least a week. They did not enter meiosis in culture, but continued to undergo mitotic proliferation.

Animals↗
PubMed2003

Regulation of aromatase gene expression in Leydig cells and germ cells.

The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase. Although somatic cells and germ cells (GC) have the capacity to produce estrogens the regulation of the CYP19 gene expression in adult rat testicular cells and specially in freshly purified Leydig cells, pachytene spermatocytes (PS) and round spermatids (RS) is not fully understood. In the present study we have analyzed the putative effects of steroid hormones, transforming growth factor beta (TGFbeta), cytokine (tumor necrosis factor alpha, TNFalpha) and dexamethasone (Dex) on CYP19 expression in these purified testicular cells from adult rat. In parallel the biological role of seminiferous tubules and Sertoli cells conditioned media on the expression of aromatase was studied. Using a highly specific quantitative competitive RT-PCR we established that testosterone (T) enhances CYP19 gene expression in Leydig cells and germ cells, and augments the estradiol outputs. The non-aromatizable androgen 5alpha-DHT induces the same effect as T on P450 aromatase (P450arom) gene expression but was inefficient on the estradiol output. In PS and RS an inhibitory effect on CYP19 gene transcription was observed with TGFbeta (1 ng/ml) alone or in combination with T. Conversely, the addition of TNFalpha (20 ng/ml) increases the P450arom transcription in PS although an inhibitory effect is observed in RS. Together with T, TNFalpha decreases the amount of P450arom mRNA in PS and RS. In PS we found that Dex regulates positively CYP19 expression and negatively in RS. Furthermore in PS a synergistic effect of Dex and TNFalpha on P450arom mRNA expression was observed whereas an additive one was recorded for RS. Therefore in germ cells TNFalpha likely enhances expression of aromatase through promoter PI.4 in PS, possibly via an AP1 site upstream the GAS element, while in RS TNFalpha requires glucocorticoids as a co-stimulator to increase CYP19 gene expression. Finally in presence of seminiferous tubules or Sertoli cell conditioned media, the amount of aromatase transcripts is increased in both Leydig cells and germ cells therefore suggesting that other locally produced modulators, yet unknown, but from Sertoli cell origin, are concerned in the regulation of the aromatase gene expression in rat testicular cells. In summary, using an in vitro model of mature rat Leydig cells, pachytene spermatocytes and round spermatids, we have shown that several factors direct the expression of the aromatase gene and it is obvious that not only promoter PII but also promoter PI.4 are concerned.

Animals↗
PubMed1997

Up-regulation and down-regulation of genes expressed in cocultures of rat Sertoli cells and germ cells.

To better understand the molecular interactions between somatic and germ cells in the mammalian testis, we have begun to analyze with mRNA differential display changes in gene expression induced by coculturing rat Sertoli cells and germ cells. We have identified 10 cDNAs that are either down-regulated or up-regulated in cocultures of germ cells and Sertoli cells. Three genes expressed in Sertoli cells and three genes expressed in germ cells were down-regulated in Sertoli cell-germ cell cocultures, whereas four genes were up-regulated in the cocultures. Northern blot analysis was used to establish the expression pattern of the mRNAs encoded by the cDNAs and to define the sizes of the differentially expressed mRNAs. Sequence analysis of the cDNAs and computer searches against the GenBank and EMBL DNA databases were used to relate the ten cDNAs to known genes. Of the three Sertoli cell cDNAs, one appeared identical to transferin, while the other two shared regions of similarity to an endoplasmic reticulum stress protein and to a pro-alpha 2 XI collagen, respectively. The three germ cell cDNAs shared sequences with fibronectin, with a basic fibroblast growth factor receptor and with an IgG gamma 2b, respectively. The four cDNAs that were up-regulated in the Sertoli-germ cell cocultures showed similarity to an isoform of casein kinase 1 delta, to an epidermal growth factor, to a statin-related protein, and to an integral membrane glycoprotein. These data demonstrate that a number of specific genes are up- and down-regulated when germ cells and Sertoli cells are cocultured, and suggest these genes are important in cell to cell communication during spermatogenesis.

Amino Acid Sequence↗
PubMed1978

Occurrence of nuage in fetal human germ cells.

Germ cells of human fetuses aged 7-13 weeks were studied. Dense fibrous material called nuage was found in the cytoplasm of human fetal germ cells. The nuage increased in frequency in the germ cells during the interval studied. In oogonia the nuage occurred much more frequently than in spermatogonia and the frequency of nuage in oogonia increased earlier than in spermatogonia. The number of nuage was continuously at a higher level in oogonia than in spermatogonia. It is suggested that these findings support the theory that the nuage may act as a germ cell determinant.

Female↗
PubMed2006

Dysfunction of the mitotic:meiotic switch as a potential cause of neoplastic conversion of primordial germ cells.

Germ cell tumours (GCT) are thought to arise as the result of a defect in early development, probably shortly after arrival of the migrating primordial germ cells (PGC) in the genital ridge when, if in a male genital ridge, the germ cells arrest in mitosis, but in a female genital ridge they enter meiosis. We suggest that dysfunction of the mitotic:meiotic switch, with cells aberrantly co-expressing functions pertinent to both states, might provide the genetic instability that could initiate tumour development. If this hypothesis is correct, GCT could arise because of disruption in the function of any one of a number of different genes involved in controlling mitosis and meiosis, rather than being dependent upon a single prominent susceptibility gene. The Notch signalling system is one candidate system for controlling the switch and we have identified expression of Notch2 and Notch4 in seminomas and carcinoma in situ. Thus those two members of the Notch family are candidates for proto-oncogenes that could play a role in GCT development. We have also identified a human homologue of the synaptonemal complex protein, SCP3, and have found its apparently aberrant expression in some established EC cell lines. One possibility is that abnormal regulation of such proteins involved in the synaptonemal complex could also lead to genetic instability in PGC and so also initiate tumour development.

Cell Cycle Proteins↗
PubMed2005

Regulation of Sertoli cell and germ cell differentation.

Unwanted childlessness affects approximately one in six couples worldwide. According to the World Health Organization, in nearly 40% of cases the cause can be attributed to the female, in 20% to the male, in 25% to both, and in 15% the cause remains unknown. The incidence of male factor infertility in the general population is approximately 7%. The majority of these men experience irreversible idiopathic infertility and cannot father children without some form of medical intervention. Male factor infertility, in addition, may be caused by testicular germ cell cancer, which is known to represent the most common cancer among young men in Western industrialized countries. There is growing evidence that this cancer originates from fetal germ cells exhibiting an aberrant programme of gene expression and that tumour progression may be favoured by an aberrant Sertoli cell-germ cell communication. The present monograph aims to shed more light on the regulation of Sertoli and germ cell differentiation. Involving knockout and transgenic mouse models, the authors focus on (a) male factor infertility that might be related to altered maturation of Sertoli cells, (b) male factor infertility that might be due to incorrect histone-to-protamine exchange in haploid spermatids, and (c) progression of testicular germ cell cancer that might be favoured by an aberrant Sertoli cell-germ cell communication.

Animals↗
PubMed1981

[Atypical intratubular germ cells and testicular germ cell tumors in children (author's transl)].

Intratubular atypical germ cells are quite frequent in seminiferous tubules of tumor-free tissue adjacent to germ cell tumors of the adult testis. Atypical germ cells are considered by several authors to be totipotent stem cells for different types of germ cell tumors. If this theory is correct, atypical germ cells should be demonrable in the vicinity of germ cell tumors of children as well. We reviewed 30 testicular germ cell tumors of children aged 6 months to 6 1/2 years (17 yolk sac tumors and 13 mature teratomas). In five cases no tumor-free testicular tissue was present. In the remaining 25 cases - 15 patients with yolk sac tumors and 10 patients with mature teratomas - no atypical germ cells, neither intra-nor extratubular in location, could be found. The question arises, therefore, whether these so-called atypical germ cells are really the precursor cells of germ cell tumors or if they represent, at least in some cases, a reactive phenomenon due to the presence of a germ cell tumor.

Child↗
PubMed1997

Primary mediastinal germ cell tumor with intratubular germ cell neoplasia of the testis--further support for germ cell origin of these tumors: a case report.

BACKGROUND: The histogenesis of extragonadal germ cell tumors remains an enigma. The majority of patients with retroperitoneal tumors are male, and careful histologic evaluation reveals preinvasive intratubular germ cell neoplasia (ITGCN) or scars in the testis suggesting a so-called "burnt out" germ cell tumor. However, in the testes of patients with primary mediastinal germ cell tumors, no ITGCN has been described in the literature to date. The authors report the first case of simultaneous germ cell neoplasia in the mediastinum and the testis, providing further insights into the biology and origin of these lesions. METHODS: The authors report the pathologic features and cytogenetic findings in an adult male with a mediastinal germ cell tumor and asymmetric testis. This patient died shortly after diagnosis. RESULTS: A locally invasive mediastinal nonseminomatous germ cell tumor was associated with ITGCN in one testis. Metastases were not present clinically or on autopsy during a detailed and systematic examination of retroperitoneal lymph nodes and other viscera. Neither an invasive germ cell tumor nor a scar was found in either testis (both testes were serially sectioned and entirely examined histologically). CONCLUSIONS: The findings of this study suggest that the mediastinal tumor is a primary neoplasm with concomitant in situ lesion in one testis, suggesting a more generalized defect of germ cell and thus providing new information about the unresolved issue of the histogenesis of extragonadal germ cell tumors. This article presents a review of the literature concerning the issues highlighted by this case and discusses the hypotheses regarding the development of extragonadal germ cell tumors.

Adult↗
PubMed2006

Are cranial germ cell tumours really tumours of germ cells?

Germ cell tumours of the brain and those that occur in the gonads are believed to share a common origin from germ cell progenitors. This 'germ cell theory' rests upon similar histopathology between these tumours in different locations and the belief that endogenous somatic cells of the brain could not give rise to the range of cell types seen in germ cell tumours. An alternative 'embryonic cell theory' has been proposed for some classes of cranial germ cell tumours, but this still relies on the misplacement of cells in the brain (in this case the earliest embryonic stem cells) during early embryonic development. Recent evidence has demonstrated that neural stem cells of the brain can also give rise to many of the cell types seen in germ cell tumours. These data suggest that endogenous progenitor cells of the brain are a plausible alternative origin for these tumours. This idea is of central importance for studies aiming to elucidate the mechanisms of tumour development. The application of modern molecular analyses to reveal how tumour cells have altered with respect to their cell of origin relies on the certain identification of the cell from which the particular tumour arose. If the identity of this cell is mistaken, then studies to elucidate the mechanisms by which the progenitor cell has been subverted from its normal behaviour will not yield useful information. In addition, it will prove impossible to generate an appropriate animal model in which to study the underlying causes of those tumours. This article makes the case that current assumptions of the origins of cranial germ cell tumours are unreliable. It reviews the evidence in favour of the 'germ cell theory' and argues in favour of a 'brain cell theory' in which endogenous neural progenitor cells of the brain are the likely origin for these tumours. Thus, the case is made that cranial germ cell tumours, like other brain tumours, arise by the transformation of progenitor cells normally resident in the brain.

Brain Neoplasms↗
PubMed2005

Chromatin remodelling and epigenetic features of germ cells.

Germ cells have the unique capacity to start a new life upon fertilization. They are generated during a sex-specific differentiation programme called gametogenesis. Maturation of germ cells is characterized by an impressive degree of cellular restructuring and gene regulation that involves remarkable genomic reorganization. These events are finely tuned, but are also susceptible to the introduction of various types of error. Because stable genetic transmission to future generations is essential for life, understanding the control of these processes has far-reaching implications for human health and reproduction.

Amino Acid Sequence↗
PubMed2003

Human Pumilio-2 is expressed in embryonic stem cells and germ cells and interacts with DAZ (Deleted in AZoospermia) and DAZ-like proteins.

Early in development, a part of the embryo is set aside to become the germ cell lineage that will ultimately differentiate to form sperm and eggs and transmit genetic information to the next generation. Men with deletions encompassing the Y-chromosome DAZ genes have few or no germ cells but are otherwise healthy, indicating they harbor specific defects in formation or maintenance of germ cells. A DAZ homolog, DAZL (DAZ-Like), is found in diverse organisms, including humans and is required for germ cell development in males and/or females. We identified proteins that interact with DAZ proteins to better understand their function in human germ cells. Here, we show that PUM2, a human homolog of Pumilio, a protein required to maintain germ line stem cells in Drosophila and Caenorhabditis elegans, forms a stable complex with DAZ through the same functional domain required for RNA binding, protein-protein interactions and rescue of Pumilio mutations in flies. We also show that PUM2 is expressed predominantly in human embryonic stem cells and germ cells and colocalizes with DAZ and DAZL in germ cells. These data implicate PUM2 as a component of conserved cellular machinery that may be required for germ cell development.

Amino Acid Sequence↗