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PubMed2000

Characterisation of Crim1 expression in the developing mouse urogenital tract reveals a sexually dimorphic gonadal expression pattern.

The Crim1 gene encodes a putative transmembrane protein with an IGF-binding protein motif and multiple chordin-like cysteine-rich repeats. In chordin, such repeats are responsible for its dorsalising activity and for binding to bone morphogenic proteins (BMPs). Crim1 displays a dynamic expression pattern in a variety of developing organs, including the CNS and the lens. We have undertaken a detailed expression pattern analysis of Crim1 in the developing mouse urogenital system. During metanephric development, Crim1 showed expression both in the ureteric tree, the early condensing mesenchyme and distal comma-shaped bodies. As the nephron elongates, Crim1 becomes expressed in the proximal end of the S-shaped bodies. Crim1 also displays a striking male-specific expression pattern in the fetal gonads, its expression strongest in the Sertoli cells of the developing testis.

Animals↗

PubMed2005

The pluripotency homeobox gene NANOG is expressed in human germ cell tumors.

BACKGROUND: The NANOG gene, a member of the homeobox family of DNA binding transcription factors, was recently identified in a screen for pluripotency-promoting genes. NANOG overexpression in murine embryonic stem cells is sufficient to maintain self-renewal and to block differentiation. The NANOG gene is located on human chromosome 12p13, a region frequently duplicated in human tumors of germ cell origin and in cultured human embryonic stem cells. Here we investigate the expression and gene copy number of NANOG in human germ cells and tumors of germ cell origin. METHODS: Immunohistochemistry and quantitative polymerase chain reaction (QPCR) were used to examine the expression and gene copy number of the human NANOG gene in germ cell tumors. RESULTS: NANOG protein was detected in germline stem cells (gonocytes) within the developing testis. Immunohistochemistry and quantitative real-time PCR analysis were used to demonstrate that NANOG is highly and specifically expressed in carcinoma in situ (CIS), embryonal carcinomas, and seminomas, but not in teratomas and yolk sac tumors. CONCLUSIONS: NANOG expression in germline stem cells (gonocytes), CIS, embryonal carcinoma, and seminoma reveals a molecular and developmental link between germ cell tumors and the embryonic cells from which they arise. Identification of NANOG as a molecular marker of undifferentiated germ cell tumors provides a novel tool for identifying and classifying tumors of germ cell origin.

Biomarkers, Tumor↗

PubMed1988

Elevated antibody titers against cytomegalovirus among patients with testicular cancer.

The epidemiology of testicular cancer (TC) has 2 distinguishing features. First, it has an unusual unimodal age-incidence curve which peaks about age 30, and decreases with increasing age. Second, risk of the disease has been consistently associated with a high standard of living inasmuch as it is a disease of young white men of generally higher social class in economically developed populations. These features suggest that risk may be related to relatively late age of exposure to common infectious agents resulting in damage to the developing testis. We evaluated this hypothesis in a serologic case-control study in which subjects were compared for both prevalence and level of antibody to the following agents: measles, mumps, rubella, varicella (VZV), herpes simplex (HSV), cytomegalovirus (CMV), toxoplasmosis, Chlamydia, and Mycoplasma hominis. The TC cases included 50 with seminoma, 50 with embryonal carcinoma, and 17 with other sub-classifications. There were 100 male controls of comparable age. No consistent differences were found for any of the non-herpes viruses. For VZV, cases generally had elevated titers, significantly so for the seminoma patients, relative risk (RR) = 6.3 (95% confidence interval, 3.0-13.3) adjusted for the titer distributions of HSV and CMV. For HSV, seminoma patients also had elevated titers, RR = 2.6 (1.0-6.4). The strongest association was with CMV. Patients had a higher prevalence rate than controls, RR = 2.0 (1.1-3.6), and a gradient of risk with titer level. Overall, those in the highest titer quartile had an RR of 4.9 compared to those with no antibody, with a significant trend (p = 0.0002). Since age at CMV infection is directly related to social class, these findings suggest that delayed exposure to CMV, resulting in a more severe infection, may be related to risk of TC. However, confounding by immune status of the cases or by other risk factors of TC could not be evaluated and may account for this observation.

Antibodies, Viral↗

PubMed2003

Involvement of the gonadal germinal epithelium during sex reversal and seasonal testicular cycling in the protogynous swamp eel, Synbranchus marmoratus Bloch 1795 (Teleostei, Synbranchidae).

The swamp eel, Synbranchus marmoratus, is a protogynous, diandric species. During sex reversal, the ovarian germinal epithelium, which forms follicles containing an oocyte and encompassing follicle cells during the female portion of the life cycle, produces numerous invaginations, or acini, into the ovarian stroma. Within the acini, the gonia that formerly produced oocytes become spermatogonia, enter meiosis, and produce sperm. The acini are bounded by the basement membrane of the germinal epithelium. Epithelial cells of the female germinal epithelium, which formerly became follicle (granulosa) cells, now become Sertoli cells in the developing testis. Subsequently, lobules and testicular ducts form. The swamp eel testis has a lobular germinal compartment in both primary and secondary males, although the germinal compartment in testes of secondary males resides within the former ovarian lamellae. The germinal compartment, supported by a basement membrane, is composed of Sertoli and germ cells that give rise to sperm. Histological and immunohistochemical techniques were used to describe the five reproductive classes that were observed to occur during the annual reproductive cycle: regressed, early maturation, mid-maturation, late maturation, and regression. These classes are differentiated by the presence of continuous or discontinuous germinal epithelia and by the types of germ cells present. Synbranchus marmoratus has a permanent germinal epithelium. Differences between the germinal compartment of the testes of primary and secondary males were not observed.

Animals↗

PubMed2001

Aromatase plays a key role during normal and temperature-induced sex differentiation of tilapia Oreochromis niloticus.

In the tilapia Oreochromis niloticus, sex is determined genetically (GSD), by temperature (TSD) or by temperature/genotype interactions. Functional masculinization can be achieved by applying high rearing temperatures during a critical period of sex differentiation. Estrogens play an important role in female differentiation of non-mammalian vertebrates. The involvement of aromatase, was assessed during the natural (genetic all-females and all-males at 27 degrees C) and temperature-induced sex differentiation of tilapia (genetic all-females at 35 degrees C). Gonads were dissected between 486--702 degree x days. Aromatase gene expression was analyzed by virtual northern and semi-quantitative RT-PCR revealing a strong expression during normal ovarian differentiation concomitant with high levels (465 +/- 137 fg/g) of oestradiol-17 beta (E2-17 beta). This was encountered in gonads after the onset of ovarian differentiation (proliferation of both stromal and germ cells prior to ovarian meiosis). Genetic males exhibited lower levels of aromatase gene expression and E2-17 beta quantities (71 +/- 23 fg/ g). Aromatase enzyme activity in fry heads established a sexual dimorphism in the brain, with high activity in females (377.9 pmol/head/hr) and low activity in males (221.53 pmol/head/hr). Temperature induced the masculinization of genetic females to a different degree in each progeny, but in all cases repression of aromatase expression was encountered. Genetic males at 35 degrees C also exhibited a repression of aromatase expression. Aromatase brain activity decreased by nearly three-fold in the temperature-masculinized females with also a reduction observed in genetic males at 35 degrees C. This suggests that aromatase repression is required in the gonad (and perhaps in the brain) in order to drive differentiation towards testis development. Mol. Reprod. Dev. 59:265-276, 2001.

Animals↗

PubMed2005

Identification of rab12 as a vesicle-associated small GTPase highly expressed in Sertoli cells of rat testis.

We examined the expression and the localization of a small GTPase, rab12, in rat testis. Northern blot analysis showed that 2.3 kb transcript of rab12 was expressed in rat testis. RT-PCR analysis indicated constant expression of rab12 throughout testis development. Immunohistochemical studies revealed that rab12 protein was highly expressed in Sertoli cells in the seminiferous tubules, while both spermatogenic germ cells and interstitial cells exhibited faint or no immunosignal for rab12. The expression pattern of rab12 in Sertoli cells varied between the tubules: its immunostaining appeared as a wheel-like pattern at stage I approximately III and as a luminal staining pattern at stage IV approximately VI, whereas the immunostaining signals were only rudimentary detected at stage VIII and thereafter (approximately stage XIV). The diversified staining pattern of rab12 in the tubules seemed to reflect either the different shape of Sertoli cells during the cycle of the seminiferous epithelium or the variant expression levels of rab12 in Sertoli cells at each stage of the tubules. In cultured rat Sertoli cells and normal rat kidney (NRK) cells, rab12 was found to be associated with small vesicles distributed throughout the cytoplasm, but not with the Golgi apparatus. When overexpressed in NRK cells, rab12-associated small vesicles were not only distributed throughout the cytoplasm but also accumulated in the perinuclear cytoplasm around centrosome. We interrupt these data as a potential role of rab12 in acceleration of vesicular transport from the cell periphery to the perinuclear centrosome region.

Animals↗

PubMed1993

Characterization and sequencing of the sex determining region Y gene (Sry) in Akodon (Cricetidae) species with sex reversed females.

The sex determining region Y gene (Sry) is the strongest candidate to be the testis determining factor gene (Tdy). Several South-American Akodon species have two varieties of Y chromosome. One type transmitted via male specimens induces testis development. The second Y variety fails to induce male gonadal differentiation and gives rise to fully fertile XY females. These variant females test positive for Sry. Moreover, sequencing of a partial open reading frame of the conserved region of Sry from males and XY females shows no sequence difference. Sry is two- to sixfold amplified in six of eight akodont species tested. Since Sry amplification was found in species having and not having XY females, amplification apparently does not in itself play a primary role in the origin of sex reversal. The development of fully fertile ovaries in XY Akodon females is not due to a deletion of Sry or to mutations in the Sry segment analyzed in this report. Sex reversal may be due to abnormal expression of this gene at the stage of gonadal differentiation. Alternatively, other genes in the sex-determining pathway may be involved. Several of the Akodon species showing Sry amplification also have amplification of Zfy, which may map to the same region of the Akodon Y chromosome.

Amino Acid Sequence↗

PubMedDate not supplied

A naturally occurring deletion in the SRY promoter region affecting the Sp1 binding site is associated with sex reversal.

Male to female sex reversal results from failure of testis development. Mutations in the SRY gene or in other genes involved in the sexual differentiation pathway are considered to cause XY gonadal dysgenesis. The majority of the mutations in the SRY described so far are located within the SRY coding region, mainly in the HMG-box conserved domain. Comparison of 5' flanking SRY gene sequences among different species indicated the presence of several putative conserved consensus sequences for different transcription regulators. In this study, we investigated a 360 bp sequence encompassing the SRY putative core promoter, in 17 patients with variable degrees of 46,XY sex reversal, which have been previously shown not to bear mutations in the SRYcoding region. Sequencing analysis of the SRYpromoter in one patient with complete XY gonadal dysgenesis revealed a three base pair deletion in one of the Sp1 binding sites. The deletion abolished Sp1 binding in vitro. This is the first report on a naturally occurring mutation affecting the Sp1 regulatory element in the SRY promoter region, which is associated with sex reversal. Additionally, upon familial investigation the father, who had 18 genital surgeries due to severe hypospadia without cryptorchidism, was found to bear the same deletion and several relatives were referred to have sexual ambiguity.

Adolescent↗

PubMed1988

Tuberculous epididymo-orchitis.

In the clinical course of epididymitis in a forty-four-year-old male patient, enlargement of ipsilateral testis developed which was difficult to distinguish clinically from testicular tumor. High inguinal orchiectomy was performed. Microscopic sections revealed many granulomas with caseous necrosis and giant cells. Tuberculous bacilli also were demonstrated in the histologic examination.

Adult↗

PubMed1988

Nuclear triiodothyronine receptors in rat Sertoli cells.

The existence of specific triiodothyronine (T3) receptors in cultured rat Sertoli cells was investigated by evaluating the affinity and capacity of nuclear binding for T3. The results demonstrate the presence of high affinity (Ka = 0.15 +/- 0.02 X 10(10) M-1), low capacity (1.35 +/- 0.07 pmol T3/mg DNA) binding sites for T3 in rat Sertoli cell nuclei. It is demonstrated that, within the developing testis, the major localization of nuclear T3 receptors is in Sertoli cells.

Animals↗

PubMed2005

Subcellular recruitment by TSG118 and TSPYL implicates a role for zinc finger protein 106 in a novel developmental pathway.

To gain insight into the function of zinc finger protein 106 (ZFP106), we analyzed its subcellular targeting and identified its interacting proteins. Although ZFP106 was detected predominantly in the fibrillar component of the nucleolus and co-localized with the nucleolar transcriptional machinery, its overexpression did not affect transcription of pre-ribosomal RNA genes. The nucleolar association of ZFP106 did neither require ongoing ribosomal RNA synthesis nor nucleolar chromatin indicating that a protein-protein interaction confines ZFP106 to the nucleolus. Deletion analysis revealed that the C-terminal WD40 repeat region functions in nucleolar targeting. This domain interacts with the product of testis-specific gene 118 (TSG118), which also co-localizes with ZFP106 in the nucleolus. Rapid downregulation of TSG118 expression during in vitro terminal differentiation coincides with a loss of nucleolar ZFP106. By its structural features and expression, TSG118 mimics nucleostemin, a nucleolar protein linked to the proliferation potential of stem cells. A two-hybrid screen with the N-terminal region of ZFP106 as bait led to the isolation of testis-specific Y-encoded-like protein (TSPYL), a member of the nucleosome assembly protein family. A frame-shift mutation in TSPYL has recently been found to cause a sudden infant death syndrome with testis dysgenesis. Specific recruitment of ZFP106 via amino acids 412-781 into TSPYL-positive nucleoplasmic bodies requires a TSPYL domain absent in the mutant protein of patients with testis dysgenesis. These results identify ZFP106 as a potential player in a novel pathway involved in testis development.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Rhox: a new homeobox gene cluster.

Homeobox genes encode transcription factors notable for their ability to regulate embryogenesis. Here, we report the discovery of a cluster of 12 related homeobox genes on the X chromosome expressed in male and female reproductive tissues in adult mice. These reproductive homeobox on the X chromosome (Rhox) genes are expressed in a cell type-specific manner; several are hormonally regulated, and their expression pattern during postnatal testis development corresponds to their chromosomal position. Most of the Rhox genes are expressed in Sertoli cells, the nurse cells in direct contact with developing male germ cells, suggesting that they regulate the expression of somatic-cell gene products critical for germ cell development. In support of this, targeted disruption of Rhox5 increased male germ cell apoptosis and reduced sperm production, sperm motility, and fertility. Identification of this family of homeobox genes provides an opportunity to study colinear gene regulation and the transcriptional control of reproduction.

Animals↗

PubMed2004

Endotoxin and proinflammatory cytokines modulate Sertoli cell proliferation in vitro.

Sertoli cells play a key role in testicular function and their final number in the adult testis determines the capacity of germ cell production. Sertoli cell proliferation, stimulated by FSH and paracrine factors, occurs only in fetal and prepubertal life and may be an important target of pathogenic influences affecting testis development. We used a Sertoli cell proliferation assay to address the question whether if bacterial endotoxin (lipopolysaccharide; LPS) and proinflammatory cytokines could influence early postnatal Sertoli cell development. LPS and tumor necrosis factor-alpha (TNF-alpha) dose-dependently stimulated proliferation of primary cultures of isolated Sertoli cells from 8- to 9-day-old rats, assessed by (3)H-thymidine and BrdU incorporation. LPS also significantly increased the number of living cells in culture, measured by supravital staining. Interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) had no direct effect on Sertoli cell growth, but were found to modulate FSH action. IL-6 increased, while IFN-gamma inhibited, FSH-induced Sertoli cell DNA-synthesis. We conclude that endotoxin and TNF-alpha are potent direct stimulators of Sertoli cell proliferation in vitro, and that IL-6 and IFN-gamma can modulate the mitogenic action of FSH on immature Sertoli cells. This may contribute to the pathogenesis of testicular damage after infections and inflammatory diseases in fetal and early postnatal life, with subsequent disturbance of adult germ cell production.

Animals↗

PubMed2004

Windows for sex-specific methylation marked by DNA methyltransferase expression profiles in mouse germ cells.

The acquisition of genomic methylation in the male germ line is initiated prenatally in diploid gonocytes, while DNA methylation in the female germ line is initiated postnatally in growing oocytes. We compared the temporal expression patterns of the DNA methyltransferases, DNMT1, DNMT3a, DNMT3b, and DNMT3l in the male and female germ lines. DNMT1 expression was examined by immunocytochemistry and Northerns with an emphasis on the prenatal period. In the female, there is a gradual down-regulation of DNMT1 protein in prenatal meiotic prophase I oocytes that is not associated with the production of an untranslated transcript, as it is in the male; these results suggest that the mechanism of meiotic down-regulation differs between the sexes. In the male, DNMT1 is unlikely to play a role in the prenatal acquisition of germ line methylation patterns since it is down-regulated in gonocytes between 14.5 and 18.5 days of gestation and is absent at the time of initiation of DNA methylation. To search for candidate DNMTs that could be involved in establishing methylation patterns in both germ lines, real-time RT-PCR was used to simultaneously study the expression profiles of the three DNMT3 enzymes in developing testes and ovaries; DNMT1 expression was included as a control. Expression profiles of DNMT3a and DNMT3l provide support for an interaction of the two enzymes during prenatal germ cell development and de novo methylation in the male. DNMT3l is the predominant DNMT3 enzyme expressed at high levels in the postnatal female germ line at the time of acquisition of DNA methylation patterns. DNMT1 and DNMT3b expression levels peak concomitantly, shortly after birth in the male, consistent with a role in the maintenance of methylation patterns in proliferating spermatogonia. Together, the results provide clues to specific roles for the different DNMT family members in de novo and maintenance methylation in the developing testis and ovary.

Animals↗

PubMed2004

SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors.

The Y chromosome gene Sry encodes a transcription factor required to initiate testis development. The related autosomal gene Sox9 is up-regulated shortly after the onset of Sry transcription and is thought essential for the differentiation of Sertoli cells. The lineage that gives rise to Sertoli cells has its origins within the coelomic epithelium (CE) of the genital ridge, but from cells also able to give rise to an interstitial cell type. It was not known at what point SRY acts in the derivation of this lineage or how the two genes interact. To investigate the identity of the cells expressing Sry, we designed two transgenes driven by the Sry promoter: one gives expression of a stable reporter, human placental alkaline phosphatase (hPLAP), while the second gives expression of a functional Myc-epitope tagged SRY protein (SRYMYC). Taking advantage of lasting hPLAP activity after transcription of the reporter gene has ceased, we could show that SryhPLAP was expressed exclusively in all cells fated to become Sertoli cells. SRYMYC-single-positive cells were first observed in the gonad and not in the CE. Subsequently, they became SRYMYC/SOX9-double-positive, but only for a few hours before turning into SOX9-single-positive cells. After the coelomic epithelial cells migrate into the gonad, there is first a decision to become interstitial or supporting cells, and then the transient expression of SRY in the latter determines their fate as Sertoli cells by up-regulating Sox9.

Alkaline Phosphatase↗

PubMed2004

Developmental expression and function of Bmp4 in spermatogenesis and in maintaining epididymal integrity.

Bone morphogenetic proteins (BMPs) play essential roles in many aspects of developmental biology. We have previously shown that Bmp7, Bmp8a, and Bmp8b of the 60A class of Bmp genes have additive effects in spermatogenesis and in maintaining the epididymal integrity of the caput and caudal regions. Here we report that Bmp4 of the Dpp class has a unique expression pattern in the developing testis and epididymis. Bmp4 heterozygous males on a largely C57BL/6 background show compromised fertility due to degeneration of germ cells, reduced sperm counts, and decreased sperm motility. More interestingly, some of these males show extensive degeneration of the epididymal epithelium in the corpus region, rather than in the caput and cauda regions as for Bmp7 and Bmp8 mutants. Thus, these genetic data reveal a region-specific requirement of different classes of BMPs for epididymal epithelium to survive and have significant implications on male reproductive health and perhaps birth control.

Animals↗

PubMed2006

Remarkable expansions of an X-linked reproductive homeobox gene cluster in rodent evolution.

Rhox is a recently identified cluster of 12 X-linked homeobox genes in mice. The expression pattern of Rhox genes during postnatal testis development corresponds to their chromosomal position, much like the colinear gene regulation of the Hox gene clusters during animal embryonic development. We here report the identification of 18 additional Rhox genes and 3 pseudogenes in mice. Comparative analyses of the mouse, rat, human, dog, cow, opossum, and chicken genomes suggest that the Rhox cluster originated in the common ancestor of primates and rodents. It subsequently underwent two remarkable expansions, first in the common ancestor of mice and rats and then in mice. Positive selection promoting amino acid substitutions was detected in some young Rhox genes, suggesting adaptive functional diversification. The recent expansions of the Rhox cluster provide an opportunity to study the mechanism and origin of colinear gene regulation, but they may also undermine the utility of mouse models for understanding the development and physiology of the human reproductive system.

Amino Acid Sequence↗

PubMed1979

Abnormalities of the vas deferens and epididymis in cryptorchid boys with congenital rubella.

Cryptorchidism was present in 12% of 316 boys with congenital rubella (CR) followed by The Roosevelt Hospital Rubella Project. Eight of these patients, age 4 through 16 yr, had a recent orchiopexy, 4 on the left, 2 on the right, and 2 bilaterally. The vasoepididymal system was absent or apparently obstructed in 60% of the 10 sides. The epididymis was abnormal in 6 instances and the vas deferens in 5. Sixty-one boys of the entire series had an intravenous pyelogram (IVP) that was significantly abnormal in 18%. The 8 patients described all had a normal IVP except for 2 who had a malrotated kidney on the involved side. In 5 of the 8, a known maternal rubella infection has occurred during the first 8 wk of gestation. As the rubella virus is known to interfere with cellular growth and tissue differentiation in early pregnancy, it apparently altered the developing testis and mesonephric duct system. Similar vasoepididymal abnormalities have been described previously in patients with uncomplicated cryptorchidism, inguinal hernia, kidney defects, cystic fibrosis and male sterility. Their presence should alert the clinician to perform an IVP and also consider a diagnosis of congenital rubella.

Adolescent↗