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PubMed2001

Postnatal development of the testis in Japanese children based on observations of undescended testes.

BACKGROUND: Little is known about the morphological aspects of the postnatal development of the testis in Japanese children. By investigating the normal development of the testis, clinicians in urology can give better strategies to their patients. In addition, the pattern of development will improve the understanding of the effect of xenoestrogens. METHODS: Biopsied testis samples of 68 patients with undescended testes aged between 2 and 21 years were examined by light microscopy. Nineteen patients with normal histology of the bilateral testes were selected for this study. For light microscopy, paraffin sections were stained with hematoxylin and eosin. In addition, using electron microscope, Epon sections stained with lead citrate and uranyl acetate were observed. Semi-thin sections stained with toluidine blue were also used for light microscopy. RESULTS: Gonocytes were observed in the testis of the 2-year-old boys. Spermatocytes developed by 4 years of age and spermatids developed by 11 years of age. The immature Sertoli-Sertoli ectoplasmic junction was observed as early as 4 years of age, and it was completed by 9 years of age. Mature myoid cells were observed by the age of 13 years. Immature Leydig cells were found at 7 years of age and the cells matured by 13 years of age. CONCLUSION: A pattern of postnatal development of the testis in Japanese children was presented.

Adolescent↗

PubMed2001

The influence of estrogen on the developing male marsupial.

The genes and hormones involved in gonadal differentiation are highly conserved between eutherians and marsupials, although the timing of the developmental events differs. In marsupials, the testis develops seminiferous cords two days after birth, and the ovaries are not distinguishable until around eight days after birth. Differentiation of the internal genitalia is controlled in marsupials, as in eutherians, by testicular testosterone and Müllerian inhibiting substance, but differentiation of the scrotum in males and mammary primordia in females is hormone-independent. Since the young are easily accessible in the pouch, it is possible to administer gonadal hormones during the period of sexual differentiation. In both Australian and South American marsupials, estradiol treatment of neonatal males can induce male-to-female gonadal sex reversal. The testicular transformations range from partial suppression of seminiferous tubule development to the development of a morphologically normal ovary depending on the stage that treatment starts. The sex-reversed testes have a clearly defined cortex and medulla, and there are significantly fewer germ cells. The germ cells are surrounded by follicle-like cells and are in the early stages of meiosis, as is normal for XX germ cells in ovaries. In normal males, germ cells only enter meiosis at the onset of puberty. As in eutherians, estrogen treatment of neonatal male marsupials prevents regression of the Müllerian ducts, which are hypertrophic. Neonatal estradiol exposure also causes hypertrophy of the prostate and urogenital sinus. Estradiol treatment also inhibits transabdominal testicular descent and many animals develop inguinal hernias. The ability of estradiol to cause testis-to-ovary sex reversal in marsupials provides a new way of studying the interactions between genes and hormones in testicular differentiation.

Animals↗

PubMed1997

Impaired spermatogenesis in the Japanese eel, Anguilla japonica: possibility of the existence of factors that regulate entry of germ cells into meiosis.

In the cultivated male Japanese eel, spermatogonia are the only germ cells present in the testis. Weekly injections of human chorionic gonadotropin (HCG) can induce complete spermatogenesis from proliferation of spermatogonia to spermiogenesis. In some cases, however, HCG injection fails to induce complete spermatogenesis. Testicular morphological observations revealed that HCG-injected eels could be classified into three types based on their testicular conditions. Type 1 eels had a well-developed testis and the milt could be acquired by hand-stripping. In type 2 eels, spermatogenesis was also induced by HCG injection, but testicular size was remarkably smaller than that of type 1 eels, and the milt could not be hand-stripped. At the end of the experiment, type 2 fish had only spermatogonia and a small amount of spermatozoa, but no spermatocytes or spermatids, in their testis. Type 3 eels had thready testis, which did not develop any germ cells during the experimental period. These results suggest that, despite elevations of plasma 11-ketotestosterone levels, HCG injections were not successful in inducing the completion of spermatogenesis in type 2 and type 3 eels. In most spermatogonia of type 2 eels, meiosis was not induced by HCG injections. Furthermore, only few mitotic divisions had occurred as evidenced by the presence of 2(3) to 2(6) late type B spermatogonia in most cysts. This suggests that spermatogonial stem cells undergo four or five, and occasionally six, mitotic divisions before the interruption of spermatogenesis in type 2 eels. It is proposed that those numbers of mitotic divisions are related to a mediator that regulates entry of spermatogonia of the Japanese eel into meiosis.

Anguilla↗

PubMedDate not supplied

[Dysgenetic male pseudohermaphroditism].

Dysgenetic male pseudohermaphroditism is the result of a defect of testis development that encompasses a large clinical heterogeneity. It is characterized by bilateral dysgenetic testis, absence of mullerian regression, ambiguous genitalia and/or stigmata of Turner's syndrome in the majority of the cases. Typically, these individuals have either a 46,XY or 45,X/46,XY karyotype. The authors present four cases of dysgenetic male psudohermaphroditism, with ages of diagnosis between 1 month and 17 years old. The first had a male phenotype with stigmata of Turner's syndrome and the others ambiguous genitalia. Two patients were 45,X/46,XY and 45X/47,XYY mosaics and the other two were 46,XY. Gonadal karyotyping showed mosaicism (45,X/46,XY) in all four cases. In the first case was programed orquidectomy; all the others assigned a male gender, with regular follow-up until the puberty.

Adolescent↗

PubMed1996

Molecular determinants of sexual differentiation.

The processes of sexual differentiation have been greatly clarified by molecular biologic discoveries over the past five years. Gonadal differentiation into a testis or ovaries is controlled by a multitude of genes beginning with SRY which is believed to represent the testis determining factor. Other genes involved include SF-1, WT-1, DAX-1, and SOX9. The fully developed testis produces Mullerian inhibiting substance and testosterone to create the male phenotype; the female phenotype develops in their absence. This hormonally-driven process also requires additional factors and appropriate receptors. Errors in this pathway may be manifested clinically as intersex disorders, and the study of these disorders has helped to further elucidate the molecular mechanisms of sexual differentiation.

Animals↗

PubMed1993

Follicle-stimulating hormone induction of steel factor (SLF) mRNA in mouse Sertoli cells and stimulation of DNA synthesis in spermatogonia by soluble SLF.

Follicle-stimulating hormone (FSH) and its intracellular mediator, cAMP, increase the mRNA levels for the Steel factor (SLF, the c-kit ligand) in cultured primary mouse Sertoli cells. The inductive effect of cAMP is more evident in cultures from 13-day-old animals than in cultures from 18-day-old animals. Analysis through the polymerase chain reaction (PCR) indicates that (Bu)2cAMP or FSH treatment increases the levels of the mRNAs for both the potentially soluble form and the transmembrane form of SLF in cultured Sertoli cells. The ratio between mRNAs encoding the potentially soluble form and the transmembrane form of SLF increases during postnatal testis development, and it is higher in cultured Sertoli cells with respect to total testis, suggesting that, under the in vitro conditions, SLF could be produced by Sertoli cells mainly as a soluble factor. Soluble recombinant SLF stimulates, in a dose-dependent fashion, thymidine incorporation in cultures of isolated germ cell populations enriched in the mitotic stages (spermatogonia), independently of the presence of serum, whereas cAMP analogs have no effect. Autoradiographic analysis shows that SLF selectively stimulates DNA synthesis in type A spermatogonia.

Alternative Splicing↗

PubMed2002

Complementary DNA cloning and characterization of rat spergen-1, a spermatogenic cell-specific gene-1, containing a mitochondria-targeting signal.

To elucidate the molecular mechanisms involved with spermiogenesis in testis, we performed differential display screening to isolate genes that are developmentally up-regulated during rat testis development. One of the cDNAs isolated by differential display was highly expressed in testis. Both reverse transcription-polymerase chain reaction and Northern blot analysis showed that the expression level of the gene developmentally increased. By screening the rat testis cDNA library, we successfully isolated rat cDNA clones encoding the entire open-reading frame of 462 base pairs coding a small protein of 154 amino acids. Because in situ hybridization revealed that the gene was specifically expressed in haploid spermatids in the rat seminiferous tubules, it was designated as spergen-1 (spermatogenic cell-specific gene-1). The recently opened database of the full-length mouse cDNA collection contains a mouse gene that is homologous to rat spergen-1. Subcellular fractionation followed by immunoblot analysis revealed that spergen-1 protein was associated with mitochondria. The transfection experiments performed in COS-7 cells suggested that spergen-1 has a N-terminal mitochondria-targeting signal. We suggest that spergen-1 might be involved in spermiogenesis by transiently associating with spermatid mitochondria.

Amino Acid Sequence↗

PubMed1999

Expression of Dmrt1 in the genital ridge of mouse and chicken embryos suggests a role in vertebrate sexual development.

Sex-determining mechanisms are highly variable between phyla. Only one example has been found in which structurally and functionally related genes control sex determination in different phyla: the sexual regulators mab-3 of Caenorhabditis elegans and doublesex of Drosophila both encode proteins containing the DM domain, a novel DNA-binding motif. These two genes control similar aspects of sexual development, and the male isoform of DSX can substitute for MAB-3 in vivo, suggesting that the two proteins are functionally related. DM domain proteins may also play a role in sexual development of vertebrates. A human gene encoding a DM domain protein, DMRT1, is expressed only in the testis in adults and maps to distal 9p24.3, a short interval that is required for testis development. Earlier in development we find that murine Dmrt1 mRNA is expressed exclusively in the genital ridge of early XX and XY embryos. Thus Dmrt1 and Sry are the only regulatory genes known to be expressed exclusively in the mammalian genital ridge prior to sexual differentiation. Expression becomes XY-specific and restricted to the seminiferous tubules of the testis as gonadogenesis proceeds, and both Sertoli cells and germ cells express Dmrt1. Dmrt1 may also play a role in avian sexual development. In birds the heterogametic sex is female (ZW), and the homogametic sex is male (ZZ). Dmrt1 is Z-linked in the chicken. We find that chicken Dmrt1 is expressed in the genital ridge and Wolffian duct prior to sexual differentiation and is expressed at higher levels in ZZ than in ZW embryos. Based on sequence, map position, and expression patterns, we suggest that Dmrt1 is likely to play a role in vertebrate sexual development and therefore that DM domain genes may play a role in sexual development in a wide range of phyla.

Amino Acid Sequence↗

PubMed1992

Sex-determining region Y (SRY) in a patient with 46,XX true hermaphroditism.

Using a polymerase chain reaction method, a search for Y-specific DNA sequences was made in samples derived from tissues of a 46,XX true hermaphrodite. We found a sequence of SRY in the ovotestis, skin and leukocytes. Other DNA sequences, which covered the pseudoautosomal boundary region, amelogenin gene and DYZ1 locus of Y-chromosome were not detected. The SRY gene detected in the patient by the polymerase chain reaction was not detected by Southern blot analysis, using the SRY fragment as a probe. These findings suggest that in the patient there is a mosaicism of cells with and without part of the Y chromosome, including the SRY sequence. As the SRY sequence was responsible for the development of the gonadal primordium to the ovotestis, SRY seems essential for gonadal differentiation in testis development.

Base Sequence↗

PubMed2002

Reduced sperm count and normal fertility in male mice with targeted disruption of the ADP-ribosylation factor-like 4 (Arl4) gene.

The ADP-ribosylation factor-like protein 4 (ARL4) is a 22-kDa GTP-binding protein which is abundant in testes of pubertal and adult rodents but absent in testes from prepubertal animals. During testis development, ARL4 expression starts at day 16 when the spermatogenesis proceeds to the late pachytene. In the adult testis, the ARL4 protein was detected in pre- and postmeiotic cells, spermatocytes, and spermatides, but not in spermatogonia and mature spermatozoa. Mouse Arl4-null mutants generated by targeted disruption of the Arl4 gene were viable and grew normally; male as well as female Arl4(-/-) mice were fertile. However, inactivation of the Arl4 gene resulted in a significant reduction of testis weight and sperm count by 30 and 60%, respectively, without reduction of litter size or frequency. It is suggested that the disruption of Arl4 produces a moderate retardation of germ cell development, possibly at the stage of meiosis.

ADP-Ribosylation Factors↗

PubMed1998

Dax1 antagonizes Sry action in mammalian sex determination.

DAX1, which encodes an unusual member of the nuclear hormone-receptor superfamily, is a gene that may be responsible for a sex-reversal syndrome in humans, referred to as dosage-sensitive sex reversal, in which XY individuals carrying duplications of Xp21, part of the small arm of the X chromosome, develop as females. XY mice carrying extra copies of mouse Dax1 as a transgene show delayed testis development when the gene is expressed at high levels, but do not normally show sex reversal. Complete sex reversal occurs, however, when the transgene is tested against weak alleles of the sex-determining Y-chromosome gene Sry. These results show that DAX1 is largely, if not solely, responsible for dosage-sensitive sex reversal and provide a model for early events in mammalian sex determination, when precise levels and timing of gene expression are critical.

Animals↗

PubMed2001

Characterization of the mouse Dazap1 gene encoding an RNA-binding protein that interacts with infertility factors DAZ and DAZL.

BACKGROUND: DAZAP1 (DAZ Associated Protein 1) was originally identified by a yeast two-hybrid system through its interaction with a putative male infertility factor, DAZ (Deleted in Azoospermia). In vitro, DAZAP1 interacts with both the Y chromosome-encoded DAZ and an autosome-encoded DAZ-like protein, DAZL. DAZAP1 contains two RNA-binding domains (RBDs) and a proline-rich C-terminal portion, and is expressed most abundantly in the testis. To understand the biological function of DAZAP1 and the significance of its interaction with DAZ and DAZL, we isolated and characterized the mouse Dazap1 gene, and studied its expression and the subcellular localization of its protein product. RESULTS: The human and mouse genes have similar genomic structures and map to syntenic chromosomal regions. The mouse and human DAZAP1 proteins share 98% identity and their sequences are highly similar to the Xenopus orthologue Prrp, especially in the RBDs. Dazap1 is expressed throughout testis development. Western blot detects a single 45 kD DAZAP1 protein that is most abundant in the testis. Although a majority of DAZAP1 is present in the cytoplasmic fraction, they are not associated with polyribosomes. CONCLUSIONS: DAZAP1 is evolutionarily highly conserved. Its predominant expression in testes suggests a role in spermatogenesis. Its subcellular localization indicates that it is not directly involved in mRNA translation.

Journal Article↗

PubMed1995

Thyroid hormone receptor beta mRNA expression in Sertoli cells isolated from prepubertal testis.

A polymerase chain reaction (PCR)-based assay was used to evaluate the expression of thyroid hormone receptor beta mRNA in Sertoli cells isolated from both prepubertal rat and piglet testes. The expression of an mRNA coding for the functional thyroid hormone receptor beta isoform, as established by the PCR assay, agrees with the presence of specific tri-iodothyronine (T3) -binding sites in the Sertoli cell nuclei of both species, as previously evaluated by displacement analysis. The results ratify the existence of a functional T3 receptor in the prepubertal testis and confirm the Sertoli cell as a specific target for thyroid hormone action on the developing testis.

Animals↗

PubMed2000

Temperature-dependent sex determination in the American alligator: expression of SF1, WT1 and DAX1 during gonadogenesis.

Sex determination in mammals and birds is chromosomal, while in many reptiles sex determination is temperature dependent. Morphological development of the gonads in these systems is conserved, suggesting that many of the genes involved in gonad development are also conserved. The genes SF1, WT1 and DAX1 play various roles in the mammalian testis-determining pathway. SF1 and WT1 are thought to interact to cause male-specific gene expression during testis development, while DAX1 is believed to inhibit this male-specific gene expression. We have cloned SF1 and DAX1 from the American alligator, a species with temperature-dependent sex determination (TSD). SF1, DAX1 and WT1 are expressed in the urogenital system/gonad throughout the period of alligator gonadogenesis which is temperature sensitive. SF1 appears to be expressed at a higher level in females than in males. This SF1 expression pattern is concordant with the observed pattern during chicken gonadogenesis, but opposite to that observed during mouse gonadogenesis. Although the observed sexual dimorphism of gonadal SF1 expression in alligators and chickens is opposite that observed in the mouse, it is probable that SF1 is involved in control of gonadal steroidogenesis in all these vertebrates. DAX1 and WT1 are both expressed during stages 22-25 of both males and females. However, there appear to be no sex differences in the expression patterns of these genes. We conclude that DAX1, WT1 and SF1 may be involved in gonadal development of the alligator. These genes may form part of a gonadal-development pathway which has been conserved through vertebrate evolution.

Alligators and Crocodiles↗

PubMed1991

Cell-cell interactions and the regulation of testis function.

Regulatory interactions have been shown to occur between all the testicular cell types considered. The paracrine factors mediating these interactions generally influence either cellular growth or differentiation. The regulation of cellular growth is essential in the developing testis and is required for the maintenance of spermatogenesis in the adult testis. The rapid rate of germinal cell proliferation and the continuous but slowed growth of the peritubular cells and Leydig cells requires the presence of specific growth factors in the adult. Therefore, cell-cell interactions have evolved that involve growth factors such as IGF, TGF-alpha, TGF-beta and NGF. Other growth factors such as FGF or less characterized components like the seminiferous growth factor (SGF) also may be involved in the paracrine regulation of testis cell growth. An alternate cellular parameter to cell growth to consider is the regulation of cellular function and differentiation. A number of endocrine agents and locally produced paracrine factors have been shown to control and maintain testis cell function and differentiation. Cell-cell interactions mediated by factors such as androgens, POMC peptides, and PModS are all primarily directed at the regulation of cellular differentiation. Therefore, the agents which mediate cell-cell interactions in the testis can generally be categorized into factors that regulate cell growth or those which influence cellular differentiation. The specific cell-cell interactions identified will likely be the first of a large number of cellular interactions yet to be investigated. Although a number of potentially important cell-cell interactions have been identified, future research will require the elucidation of the in vivo physiological significance of these interactions. The existence of different cell types and potential cell-cell interactions in a tissue implies that the actions of an endocrine agent on a tissue will not simply involve a single hormone and single cell. The endocrine regulation of testis function will have effects on cell-cell interactions and be affected by local cell-cell interactions. The ability of LH to influence Leydig cell androgen production promotes a cascade of interactions mediated through several cell types to maintain the process of spermatogenesis. FSH actions on Sertoli cells also promote cell-cell interactions that influence germinal cell development, peritubular myoid cell differentiation and Leydig cell function. Therefore, elucidation of the endocrine regulation of testis function requires an understanding of the local cell-cell interactions in the testis.

Animals↗

PubMed1998

Candidate genes in complete and partial XY sex reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1.

The sexual phenotype is established in three steps: (1) the sex chromosome constitution; (2) the differentiation of the gonads; and (3) the response of the internal and external genitalia to the hormones produced by the differentiated gonads. Errors that occur at any of these stages can result in defective sexual differentiation. Therefore the investigation of patients with abnormalities of testis development will help elucidate the mechanisms of sex determination and gonadal differentiation. It was in this way that SRY. the primary testis determining gene was identified. De novo mutations in SRY, result in gonadal dysgenesis by disrupting the DNA-binding activity of the SRY protein. However, only 20% of cases of gonadal dysgenesis, are explained by mutations in SRY or its flanking sequences. Therefore, there are several pieces to this puzzle yet to be discovered and it is hoped that mutation analysis of other genes implicated in gonadal development and differentiation may shed some light on aetiology of gonadal dysgenesis in the remaining 80% of cases.

Animals↗

PubMed1996

Three daily melatonin infusions alter gonadal development but not GnRH neuron number in the medial preoptic area or diagonal band of Broca in Siberian hamsters.

Among juvenile Siberian hamsters reproductive development is associated with an increased number of unipolar GnRH-immunoreactive neurons in the diagonal band of Broca and medial preoptic area. In the present study, GnRH neuron morphology was assessed in male juvenile hamsters which were treated with three daily melatonin (MEL) infusions to initiate or delay gonadal development. Hamsters gestated in short days were transferred to constant light (LL) at day 14 of age and infused on days 18-20 with MEL for 6 h/day. This treatment stimulated testis development compared to that in saline-infused controls. By contrast, testis growth was suppressed by three 12 h MEL infusions in long-day gestated hamsters in LL from day 14. The number of unipolar and bipolar GnRH neuron subtypes was the same irrespective of MEL infusion or preweaning photoperiod. Thus, gonadal response to three MEL infusions is independent of changes in GnRH neuron number.

Animals↗

PubMed2001

Testis determination in mammals: more questions than answers.

In humans, testis development depends on a regulated genetic hierarchy initiated by the Y-linked SRY gene. Failure of testicular determination results in the condition termed 46,XY gonadal dysgenesis (GD). Several components of the testis determining pathway have recently been identified though it has been difficult to articulate a cascade with the known elements of the system. It seems, however, that early gonadal development is the result of a network of interactions instead of the outcome of a linear cascade. Accumulating evidence shows that testis formation in man is sensitive to gene dosage. Haploinsufficiency of SF1, WT1 and SOX9 is responsible for 46,XY gonadal dysgenesis. Besides, data on SRY is consistent with possible dosage anomalies in certain cases of male to female sex reversal. 46,XY GD due to monosomy of distal 9p and 10q might also be associated with an insufficient gene dosage effect. Duplications of the locus DSS can lead to a failure of testicular development and a duplication of the region containing SOX9 has been implicated in XX sex reversal. Transgenic studies in mouse have shown, however, that this mammal is less sensitive to gene dosage than man. Here, we will try to put in place the known pieces of the jigsaw puzzle that is sex determination in mammals, as far as current knowledge obtained from man and animal models allows. We are certain that from this attempt more questions than answers will arise.

Animals↗