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Seminiferous tubules from 5 day-old rats maintained in a semi-solid culture system were examined for 4, 8 or 12 days. Morphometric and ultrastructural studies show a significant increase in the seminiferous tubule diameter and normal Sertoli cell differentiation. All the germinal cells degenerate except the spermatogonia.
Sumoylation affects multiple cellular events, including chromatin inactivation and transcriptional repression. Our data provide the first characterization of small ubiquitin-related modifier-1 (SUMO-1) expression during human spermatogenesis by the use of high-resolution cellular SUMO-1 bioimaging. During human meiotic prophase, SUMO-1 localizes to sex chromosomes and centromeric and pericentromeric chromatin. As human spermatocytes progress toward the end of prophase in meiosis I, SUMO-1 is no longer detected within the sex body and pericentromeric heterochromatin but localizes exclusively to centromeres. SUMO-1 localization along sex chromosome axes, pseudoautosomal region, and centromeres of both chromosomes supports a role for SUMO-1 sumoylation in epigenetic events occurring over the entire sex body, e.g., meiotic sex chromosome inactivation and chromatin condensation. Centromeric SUMO-1 throughout meiotic prophase suggests a role in centromeric chromatin condensation and/or other centromere/kinetochore functions. SUMO-1 is likely involved in both facultative and constitutive heterochromatin processes in spermatocytes. Haploid round spermatids show a consistent association of SUMO-1 with centromeric clusters. During spermatid elongation, SUMO-1 localizes in the manchette perinuclear ring. Steroidogenic Leydig cells show some cytoplasmic but strong nuclear and perinuclear SUMO-1. Peritubular myoepithelial cell SUMO-1 colocalizes with centromeric heterochromatin. In epithelial Sertoli cells, when associated with centromeric heterochromatin, SUMO-1 is adjacent but not colocalized with the nucleolus. Male germ cells demonstrate no SUMO-1 nucleolar association. Human and rodent Sertoli cells consistently show an inverse correlation between androgen receptor (AR) and SUMO-1 expression and compartmentalization. Sertoli cells from certain infertile patients, however, showed greatly decreased SUMO-1 and AR. Our data suggest that human testicular SUMO-1 has specific functions in heterochromatin organization, meiotic centromere function, and gene expression.
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The ultrastructure and developmental fate of the fetal generation of Leydig cells of the rat testis was studied from the 17th day of fetal life up to 100 days after birth. The number of fetal Leydig cells per testis was determined by light microscopic morphometric analysis of semithin plastic sections. In fetal testes (days 17-22 postconception), Leydig cells exhibited a characteristic ultrastructure, containing smooth endoplasmic reticulum, many lipid inclusions and glycogen. Testes of 17-day-old fetuses contained about 25 x 10(3) fetal Leydig cells, rapidly increasing to 90 x 10(3) per testis in 21-day-old fetuses. After birth, fetal Leydig cells per testis remained relatively constant up to 2 weeks (80-90 x 10(3) per testis) and were identified by light and electron microscopy which showed their numerous lipid inclusions, their tendency for clustering and their association with interstitial tissue fibroblasts which partly encapsulated the fetal Leydig cells. From 21-100 days after birth, fetal Leydig cell numbers were quite variable with a mean of 45-60 x 10(3) per testis. These results are the first to show that the fetal generation of Leydig cells persist in the adult testis and do not undergo early postnatal degeneration or dedifferentiation into other interstitial cells. The simultaneous occurrence of the fetal Leydig cells and the adult population of Leydig cells indicates that these cells are distinct cell generations which are developmentally unrelated.
The major new developments in the diagnosis of testicular tumours over the last 11 years consist of imaging techniques and tumour markers. Doubtful clinical diagnoses of testicular tumours can now be clarified as a result of progress and diffusion of ultrasonography. Ultrasonography, a reliable (90%) and non-invasive examination, is more of a diagnostic aid than a decisive element, except in a few special cases. At the present time, magnetic resonance imaging is of no value in the diagnosis of testicular tumours. Alpha-foetoprotein and human chorionic gonadotrophin are the two essential markers for the follow-up, rather than for the diagnosis, of a testicular tumour. Lactate dehydrogenase and placental alkaline phosphatase are useful, especially in the seminomas, but are much less specific. The other markers studied have either not proven to be of any clinical value or are still in the field of research. Computed tomography appears to be gradually replacing lymphography for lymph node staging. The combination of the two examinations reduces the number of false negatives (10%) at the price of a higher number of false positives (38%). The diagnosis of testicular cancer can sometimes be made at the stage of carcinoma in situ, a precancerous lesion which progresses towards an invasive tumour in one half of cases. The practical indications for screening for carcinoma in situ are still controversial.
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The sources of origin and the peculiarities of formation of the seminal ducts and rete testis during the prenatal period of ontogenesis in man were studied. It has been established that the seminal duct sand the ducts of the rete testis form from the cellular cords of the coelomic epithelium and the primordial germ cells which appear simultaneously in the septum of the testis and the primordial germ cells which appear simultaneously in the septum of the testis and central part of its parenchyma in the embryos, 13.0--17.0 mm long. By plastic and graphic reconstruction, as well as by methods of subtle preparation under binocular microscope MBC-I control it was revealed that the seminal ducts anastomosed between themselves both within the limits of one and the adjacent lobules. The ducts of the rete testis do not form anastomoses, but superimpose over one another, creating an impression of a rete. Approaching the tunica albuginea they merge, continuing into the cuctuli efferentes testis.
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Hemicastration of rams at 1 week of age resulted in compensatory growth of the remaining testis. This was associated with an increase in the concentration of FSH in peripheral plasma which was maintained until the rams were approximately 10 weeks old. Plasma concentrations of LH were similar in both entire and hemicastrated lambs during this period. Pulsatile release of LH was observed in all rams from approximately 6 weeks of age onwards. The frequency of these pulses increased and the size of each pulse declined as the animals grew older. At 16 weeks pulsatile release was almost undetectable and the basal levels of LH had increased. The increased concentration of FSH in plasma was related to the size of the remaining testis but not to its development. The return of the plasma concentration of FSH to values similar to those found in entire rams preceded the appearance of a lumen or of any primary spermatocytes in the seminiferous tubules. Restricting the development of the remaining testis in hemicastrated rams, by trapping it in the inguinal region, did not alter the FSH response to hemicastration. The administration of gonadotrophin releasing hormone (10 microgram) at 10, 13 and 18 weeks of age provoked release of similar quantities of LH in both entire and hemicastrated rams. There was also a substantial release of FSH at 10 weeks of age but this response declined with age and by 18 weeks there was little FSH released in any of the animals. This loss of response occurred earlier in the hemicastrated rams. The data suggest that in prepubertal rams the release of FSH but not of LH is restricted by a substance produced by the developing Sertoli cells.
Androgen receptor-interacting protein 4 (ARIP4) belongs to the SNF2 family of proteins involved in chromatin remodeling, DNA excision repair, and homologous recombination. It is a DNA-dependent ATPase, binds to DNA and mononucleosomes, and interacts with androgen receptor (AR) and modulates AR-dependent transactivation. We have examined in this study the expression and cellular localization of ARIP4 during postnatal development of mouse testis. ARIP4 was detected by immunohistochemistry in Sertoli cell nuclei at all ages studied, starting on day 5, and exhibited the highest expression level in adult mice. At the onset of spermatogenesis, ARIP4 expression became evident in spermatogonia, pachytene, and diplotene spermatocytes. Immunoreactive ARIP4 antigen was present in Leydig cell nuclei. In Sertoli cells ARIP4 was expressed in a stage-dependent manner, with high expression levels at stages II-VI and VII-VIII. ARIP4 expression patterns did not differ significantly in testes of wild-type, follicle-stimulating hormone receptor knockout, and luteinizing hormone receptor knockout mice. In testes of hypogonadal mice, ARIP4 was found mainly in interstitial cells and exhibited lower expression in Sertoli and germ cells. In vitro stimulation of rat seminiferous tubule segments with testosterone, FSH, or forskolin did not significantly change stage-specific levels of ARIP4 mRNA. Heterozygous ARIP4(+/-) mice were haploinsufficient and had reduced levels of Sertoli-cell specific androgen-regulated Rhox5 (also called Pem) mRNA. Collectively, ARIP4 is an AR coregulator in Sertoli cells in vivo, but the expression in the germ cells implies that it has also AR-independent functions in spermatogenesis.
Although the adult mouse Leydig cell (LC) has been considered refractory to cytotoxic destruction by ethane dimethanesulfonate (EDS), the potential consequences of exposure during reproductive development in this species are unknown. Herein pregnant CD-1 mice were treated with 160 mg/kg on Gestation Days 11-17, and reproductive development in male offspring was evaluated. Prenatal administration of EDS compromised fetal testosterone (T) levels, compared with controls. EDS-exposed pups recovered their steroidogenic capacities after birth because T production by hCG-stimulated testis parenchyma from prepubertal male offspring was unchanged. However, prepubertal testes from prenatally exposed males contained seminiferous tubules (STs) devoid of germ cells, indicating a delay in spermatogenesis. In adults, some STs in exposed males still contained incomplete germ cell associations corroborating observed reductions in epididymal sperm reserves, fertility ratios, and litter size. Morphometry revealed an EDS-induced increase in interstitial area and a concomitant decrease in ST area, but stereology revealed an unexpected decrease in the number and size of the LCs per testis in exposed males. Paradoxically, there was an increase in both serum LH and T production by adult testis parenchyma, indicating that the LCs were hyperstimulated. These data demonstrate permanent lesions in LC development and spermatogenesis caused by prenatal exposure in mice. Thus, although adult mouse LCs are insensitive to EDS, EDS appears to have direct action on fetal LCs, resulting in abnormal testis development.
Inhibin is a gonadal hormone which is composed of an alpha-subunit and one of two related beta-subunits (betaA, betaB). Inhibin is important for pituitary FSH regulation, normal follicle development and maintenance of the estrous cycle in the female, whereas the role of inhibin in the male is less clear. Thus, we examined the expression of the inhibin-alpha gene in testis during sexual maturation in male mice, to try to gain insight into its functions in the male. Male mice of the ICR strain attained fertility at 6 weeks of age, and histological analysis revealed that a functional testis was formed, with seminiferous tubules which contain mature sperm and with an abundant population of Leydig cells. Parallel with this sexual maturation, inhibin-alpha subunit protein synthesis increased, whereas synthesis of the activin betaA and activin betaB followed with a delayed time course. Inhibin-alpha mRNA also increased during this critical period, and this corresponded to a change in the methylation status of the inhibin-alpha gene. Taken together, our data reveal that activation of inhibin-alpha gene during testis development correlated with the histological maturation of the testis and the acquisition of fertility in male mice.
Despite 12 yr since the discovery of SRY, little is known at the molecular level about how SRY and the SRY-related protein, SOX9 [SRY-related high-mobility group (HMG) box 9], initiate the program of gene expression required to commit the bipotential embryonic gonad to develop into a testis rather than an ovary. Analysis of SRY and SOX9 clinical mutant proteins and XX mice transgenic for testis-determining genes have provided some insight into their normal functions. SRY and SOX9 contain an HMG domain, a DNA-binding motif. The HMG domain plays a central role, being highly conserved between species and the site of nearly all missense mutations causing XY gonadal dysgenesis. SRY and SOX9 are architectural transcription factors; their HMG domain is capable of directing nuclear import and DNA bending. Whether SRY and SOX9 activate testis-forming genes, repress ovary-forming genes, or both remains speculative until downstream DNA target genes are identified. However, factors that control SRY and SOX9 gene expression have been identified, as have a dozen sex-determining genes, allowing some of the pieces in this molecular genetic puzzle to be connected. Many genes, however, remain unidentified, because in the majority of cases of XY females and in all cases of XX males lacking SRY, the mutated gene is unknown.
Formation and differentiation of a gonad depend on finely controlled interactions between germ cells and various types of somatic cells. These interactions already begin when the germ cells start migrating toward the gonadal ridge. Reaching the presumptive gonadal area on the mesonephros, the germ cells join with the mesonephric-derived cells. These mesonephric cells are probably the precursors of the steroid-producing cells. A crucial event for gonadal function is the enclosure of germ cells and somatic cells in specific germ cell compartments. Survival and differentiation of the germ cells depend on this separation. Differentiation of the steroid-producing cells depends in turn on remaining outside the cell compartments. The mechanisms directing the gonad to develop into a testis or an ovary are still obscure, but specific gene products from the sex chromosomes probably play a basic role in gonadal sex differentiation.
Dmrt1 is a recently described gene that is expressed exclusively in the testis and is required for postnatal testis differentiation. Here we describe the expression of Dmrt1 in postnatal rat testis and Sertoli cells. RNase protection analysis was used to examine Dmrt1 messenger RNA (mRNA) levels in intact testis during postnatal development and in primary cultures of Sertoli cells under various culture conditions. We show that Dmrt1 mRNA levels rise significantly beginning approximately 10 days after birth and remain elevated until after the third postnatal week. Thereafter, mRNA levels drop coincident with the proliferation of germ cells in the testis. In freshly isolated Sertoli cells, Dmrt1 mRNA levels were robust but decreased significantly when the cells were placed in culture for 24 h. Treatment of Sertoli cells with either FSH or 8-bromo-cAMP resulted in a significant rise in Dmrt1 mRNA levels. This cAMP response was sensitive to treatment with the transcriptional inhibitor actinomycin D but not to the translational inhibitor cycloheximide. The cAMP-dependent rise in Dmrt1 mRNA also required activation of protein kinase A, as mRNA induction was sensitive to the inhibitor H89. Studies also show that Dmrt1 expression was inhibited by phorbol esters (PMA) but only modestly effected by serum.
Gonadal development in fowls aged from 1 day to more than 4.5 years was studied in 63 ZZW and 16 ZZZ triploid crossbreds and compared with normal diploid males (ZZ) and females (ZW). In the ZZW fowl, the right gonad developed into a testis (although this occurred earlier in the ZZ genotype), and a structurally-abnormal excurrent duct system containing some malformed spermatids and spermatozoa was associated with the gonad of young adults. The left gonad was an ovotestes at hatching and no excurrent ducts were associated with it. The ovarian component was much less developed than that in the ZW genotype-it started to degenerate by 1 week of age, and most of the oocytes had disappeared by about 3 weeks of age. The seminiferous tubules developed in the medullary region, but only abnormal spermatozoa were produced. Leukocytes infiltrated both gonads at about 9 months of age and the seminiferous epithelium had degenerated in most fowls over 1 year old. In ZZZ fowl, gonadal and excurrent duct development was normal, but occurred earlier than in the ZZ genotype. However, meiosis and spermiogenesis were abnormal and malformed spermatozoa were produced. The heads of spermatozoa from the ducts deferens were about 1.4-times longer in the ZZZ genotype than in the ZZ genotype, indicating that the former may be producing some diploid spermatozoa.
Since the development of surgery, the possibility of testis transplantation has fascinated man for centuries. Hunter and Berthold are considered to be the most important investigators in this field and, in addition, to be the founders of modern endocrinology. The association of testis transplantation with rejuvenation led to widespread popularity for this treatment in the first three decades of the twentieth century. At the same time, controversies concerning the aim of the treatment have coloured the early years of endocrinology. In the 1960s renewed interest in the subject arose for experimental reasons, leading to the development of microsurgical techniques for autotransplantation of high-lying undescended testes in children. Homologous testis transplantation has never become a subject of great interest, probably for ethical reasons. This possible treatment for hypogonadism, however, has been developed experimentally and has been performed in man only in Russia and China, evidently with success. The details of these studies and their outcomes are discussed.
Sex determination, the step at which differentiation of males and females is initiated in the embryo, is of central importance to the propagation of species. There is a remarkable diversity of mechanisms by which sex determination is accomplished. In general these mechanisms fall into two categories: Genetic Sex Determination (GSD), which depends on genetic differences between the sexes, and Environmental Sex Determination (ESD), which depends on extrinsic cues. In this review we will consider these two means of determining sex with particular emphasis on two species: a species that depends on GSD, Mus musculus, and a species that depends on ESD, Trachemys scripta. Because the structural organization of the adult testis and ovary is very similar across vertebrates, most biologists had expected that the pathways downstream of the sex-determining switch would be conserved. However, emerging data indicate that not only are the initial sex determining mechanisms different, but the downstream pathways and morphogenetic events leading to the development of a testis or ovary also are different.