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PubMed1999

Cryptorchidism in mice mutant for Insl3.

Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.

Animals↗

PubMed2003

TGF-betas: their role in testicular function and Sertoli cell tight junction dynamics.

Transforming growth factor-betas (TGF-betas) are known to regulate multiple physiological functions in the testis, which include spermatogenesis, Leydig cell steroidogenesis, extracellular matrix synthesis and testis development. More recent studies have shown that TGF-beta3 also regulates Sertoli cell tight junction (TJ) dynamics in vitro via the p38 mitogen-activated protein (MAP) kinase pathway, suggesting that this cytokine plays a crucial role in regulating the opening and closing of the blood-testis barrier (BTB). This in turn regulates the passage of pre-leptotene and leptotene spermatocytes across the BTB at stages VIII-XI of the seminiferous epithelial cycle. This review summarizes recent advances of studies on TGF-betas in the testis, highlighting their regulatory role in TJ dynamics.

Animals↗

PubMed1990

Developmental regulation of metallothionein mRNA, zinc and copper levels in rainbow trout, Salmo gairdneri.

The metallothionein (MT) gene expression profile was followed in rainbow trout during early embryo development and in liver and gonads during the period of sexual maturation. The hepatic MT mRNA levels increase at the end of sexual maturation in both male and female rainbow trout. Although both isoforms of MT mRNA accumulate in the liver, there is a preferential increase in MT-A in the female liver. Concomitantly with this increase in MT there is a redistribution of zinc and copper to MT. In the juvenile female there is an abundance of MT mRNA in the ovaries. This is correlated to high levels of zinc in the MT fraction upon Sephadex G-75 chromatography. During ovary development the MT mRNA levels and the MT-bound zinc levels drop, with an increase in zinc being bound to high-molecular-mass proteins. At ovulation most of the zinc is found in the membrane portion upon centrifugation. In contrast to the ovaries, there are no apparent changes in either trace metal distribution or MT mRNA levels during testis development. In the developing embryo there is an increase in MT-bound copper at gastrulation. This is accompanied by an increase in both isoforms of MT mRNA. At hatch both the copper and zinc levels increase in the MT fraction, with a concomitant increase in mainly MT-A mRNA. These findings indicate that the variations in MT mRNA levels during development are closely associated with metal regulation.

Animals↗

PubMed2003

Progeny from sperm obtained after ectopic grafting of neonatal mouse testes.

Ectopic grafting of testicular tissue is a promising new approach that can be used to preserve testicular function. This technique has been used recently to differentiate the neonatal testes of different species, up to the level of complete spermatogenesis. This approach can be applied successfully to generate live progeny using sperm extracted from grafts originating from testes of newborn donors. The sperm are capable of supporting normal development and producing fertile male and female offspring after intracytoplasmic injection into mouse oocytes and embryo transfer into surrogate mothers. The grafted tissue was also capable of significantly normalizing reproductive hormone levels in the castrated recipients. This technique presents new avenues for experimentation. The recipient mouse can be regarded as a living incubator and a culture system of testicular tissue, allowing the experimental manipulation of several aspects of testis development and spermatogenesis. The successful generation of pups indicates that this technique can be used to study the testicular phenotype and to breed mutant or transgenic mouse strains with lethal postnatal phenotypes. The ability to generate sperm from the germ line ex vivo also paves the way for the development of new strategies for preserving fertility in boys undergoing cancer therapy.

Animals↗

PubMed1991

Expression of the c-kit proto-oncogene in the murine male germ cells.

The proto-oncogene c-kit encodes a transmembrane protein tyrosine kinase receptor. The c-kit gene has recently been shown to be allelic with the W locus. Mutations at the white spotting locus (W) affect various aspects of hematopoiesis, melanogenesis and gametogenesis during development and in the adult animal. We have investigated the expression of the proto-oncogene c-kit in mouse testicular cell populations. The c-kit mRNA was found to be expressed at high levels in spermatogonia, and at lower levels in meiotic pachytene spermatocytes. Moreover, two novel testis-specific c-kit transcripts of 3.5 and 2.3 kb are present in postmeiotic haploid germ cells. These results suggest a role of c-kit not only during testis development in the embryo, but also throughout all stages of male germ cell development after birth.

Animals↗

PubMedDate not supplied

Expression of 140-kDa neural cell adhesion molecule in developing testes in vivo and in long-term Sertoli cell-gonocyte cocultures.

The basis for cell-cell adhesion in the seminiferous epithelium of the developing testis is doubtless critical in supporting events that are essential for the onset and maintenance of normal spermatogenesis. In this study, we applied immunoblotting and immunolocalization approaches for the following reasons: 1) to ask whether neural cell adhesion molecule (NCAM) underlies cell-cell interactions in vivo, as we previously showed for cells in vitro, 2) to characterize the isoform or isoforms of NCAM expressed during testicular development, and 3) to study NCAM expression in long-term Sertoli cell-gonocyte cocultures and to compare and contrast this pattern of expression with that in vivo. Our findings indicate that NCAM is found ubiquitously at cell-cell interfaces within the seminiferous cord from birth through day 10 and thereafter is restricted to interstitial cells. Moreover, only polysialic acid-negative 140-kDa NCAM is expressed in the testis or in coculture, an isoform whose properties are compatible with the concept of NCAM as both a direct modifier of cell function and an indirect influence on cell responses mediated by other external factors. In addition, we found that germ cells, potentially gonocytes or Type A spermatogonia, persist in long-term cocultures maintained for 15 days after isolation from 5-day-old rat pups and that NCAM continues to be expressed at high levels in these cultures. This observation is in marked contrast to our observation that NCAM gradually decreases and eventually disappears in vivo by postnatal day 15. Thus, our findings indicate that 140-kDa NCAM is prominent in neonatal testes but is down-regulated by as yet unidentified mechanisms thereafter. Our findings also indicate that down-regulation of NCAM fails to occur in hormone- and serum-free Sertoli cell-germ cell cocultures.

Animals↗

PubMed2002

Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis.

During embryogenesis, primordial germ cells (PGCs) have the potential to enter either spermatogenesis or oogenesis. In a female genital ridge, or in a non-gonadal environment, PGCs develop as meiotic oocytes. However, male gonadal somatic cells inhibit PGCs from entering meiosis and direct them to a spermatogenic fate. We have examined the ability of PGCs from male and female embryos to respond to the masculinising environment of the male genital ridge, defining a temporal window during which PGCs retain a bipotential fate. To help understand how PGCs respond to the male gonadal environment, we have identified molecular differences between male PGCs that are committed to spermatogenesis and bipotential female PGCs. Our results suggest that one way in which PGCs respond to this masculinising environment is to synthesise prostaglandin D(2). We show that this signalling molecule can partially masculinise female embryonic gonads in culture, probably by inducing female supporting cells to differentiate into Sertoli cells. In the developing testis, prostaglandin D(2) may act as a paracrine factor to induce Sertoli cell differentiation. Thus part of the response of PGCs to the male gonadal environment is to generate a masculinising feedback loop to ensure male differentiation of the surrounding gonadal somatic cells.

Animals↗

PubMed2001

Evidence for FSH-dependent upregulation of SPATA2 (spermatogenesis-associated protein 2).

Here we report the cloning and characterization of a novel cDNA named spata 2. SPATA2 is the ortholog of PD1, a human testicular protein which has been suggested to play a role in spermatogenesis. The spata 2 sequence reveals an open reading frame encoding a protein of 511 amino acids. Northern blot analysis with rat mRNA demonstrated two distinct transcripts of 2.2 and 4.0 kb. Tagging recombinant SPATA2 with the green fluorescent protein (GFP) and expressing the chimeric polypeptide in HLtat transfected cells indicated that SPATA2 is located in the nucleus. RT-PCR analysis revealed that spata 2 mRNA is expressed in the testis and to a lesser extent in the brain while skeletal muscle and kidney showed a barely visible signal. The same analysis demonstrated that isolated Sertoli cells express spata 2 mRNA. Treating Sertoli cells with FSH in vitro induced remarkable changes in the steady-state level of spata 2 mRNA in a time-dependent manner. In developing testis spata 2 transcripts were first detected 10 days post partum and expression levels increased steadily with age. The ability of FSH to stimulate spata 2 mRNA expression as well as its developmental expression suggests that this protein might play a role in regulating spermatogenesis and thus, according to the Gene Nomenclature Committee, we propose the name SPATA2 (Spermatogenesis associated protein 2) for this protein (or gene).

Amino Acid Sequence↗

PubMed1990

Ontogeny and pituitary regulation of testicular growth hormone-releasing hormone-like messenger ribonucleic acid.

The testis is rich in central nervous system-type neuropeptides, including a GH-releasing hormone (GHRH)-like substance. We examined the ontogeny and pituitary regulation of testicular GHRH-like mRNA (t-GHRH mRNA) and compared this to expression of insulin-like growth factor-I (IGF-I) and IGF-II mRNA in developing testis. t-GHRH mRNA was measured by dot blot hybridization and quantitated using a hypothalamic GHRH cRNA standard. t-GHRH mRNA was not detectable in Northern blots in fetal testis on day 19 of gestation, but was present in low but detectable amounts in testicular dot blots on day 2 of life (0.44 pg/micrograms total RNA). Levels of the RNA increased beginning on day 21 (1.72 +/- 0.23 pg/micrograms total RNA) and reached adult levels by day 30 (4.96 +/- 0.84 pg/micrograms total RNA). The GHRH species on Northern analysis was about 1750 nucleotides at all ages examined; there was a larger species of about 3350 nucleotides seen on days 65 and 90. There was no correlation between the ontogeny of t-GHRH mRNA and either IGF-I or IGF-II mRNAs, which were maximally expressed in the testes of day 2 animals and decreased with age. To examine the influence of the pituitary gland on t-GHRH mRNA, levels of the mRNA were measured in the tests of hypophysectomized animals and age-matched controls. In animals hypophysectomized on day 21 and killed on day 42 and in animals hypophysectomized on day 42 and killed on day 63, there was marked diminution of t-GHRH mRNA (19 +/- 5% and 9 +/- 2% of age-matched controls, respectively). In contrast, in animals hypophysectomized on day 65 and killed on either day 80 or 90, there was a much smaller difference in levels of t-GHRH mRNA compared to values in control animals (73 +/- 20%). This was unlike the effect of hypophysectomy on testicular IGF-I mRNA, where uniform diminution was seen in all three groups. Because GH is important in the regulation of hypothalamic GHRH mRNA, we examined the effects of administration of recombinant human GH on the reinduction of t-GHRH mRNA after hypophysectomy and compared this to the reinduction of IGF-I mRNA. Neither t-GHRH mRNA nor testicular IGF-I mRNA increased in hypophysectomized animals treated with GH. Our results indicate that t-GHRH mRNA is developmentally regulated, and that the hypothalamic-pituitary axis is important in its expression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1999

Temperature-dependent sex determination in the American alligator: AMH precedes SOX9 expression.

Gonadal morphogenesis is very similar among mammals, birds, and reptiles. Despite this similarity, each group utilises quite different genetic triggers for sex determination. In mammals, testis development is initiated by action of the Y-chromosome gene SRY. Current evidence suggests that SRY may act together with a related gene, SOX9, to activate another gene(s) in the pathway of testicular differentiation. A downstream candidate for regulation by SRY and SOX9 is AMH. In mouse, Sox9 is expressed in the Sertoli cells of the embryonic testis and it precedes the onset of Amh expression. During mouse gonadogenesis, Amh is confined to the embryonic testis, although it later shows postnatal expression in the ovary. Reptiles such as the American alligator, which exhibit temperature-dependent sex determination (TSD) do not have dimorphic sex chromosomes and apparently no SRY orthologue. SOX9 is expressed during testis differentiation in the alligator; however, it appears to be expressed too late to cause testis determination. Here we describe the cloning and expression of the alligator AMH gene and show that AMH expression precedes SOX9 expression during testis differentiation. This is the opposite to that observed in the mouse where SOX9 precedes AMH expression. The data presented here, as well as findings from recent expression studies in the chick, suggest that AMH expression is not regulated by SOX9 in the non-mammalian vertebrates.

Alligators and Crocodiles↗

PubMed2006

A testis-specific and testis developmentally regulated tumor protein D52 (TPD52)-like protein TPD52L3/hD55 interacts with TPD52 family proteins.

Tumor protein D52-like proteins (TPD52) are small coiled-coil motif bearing proteins that were first identified in breast cancer. TPD52 and related proteins have been implicated in cell proliferation, apoptosis, and vesicle trafficking. To date, three human TPD52 members had been identified, named hD52 (TPD52), hD53 (TPD52L1), and hD54 (TPD52L2). The most important characteristic of the protein family is a highly conserved coiled-coil motif that is required for homo- and heteromeric interaction with other TPD52-like proteins. Herein, we identified a novel TPD52-like sequence (TPD52L3, or hD55) in human testis using cDNA microarray. Sequence analysis of the deduced protein suggests that hD55 contains a coiled-coil motif and is highly conserved compared with other TPD52-like sequences. Yeast two-hybrid and GST pull-down assays revealed that hD55 interacts with hD52, hD53, hD54, and itself. cDNA microarray detection found that hD55 was expressed at 5.6-fold higher levels in adult testis than in fetal testis. Additionally, the expression profile shows that hD55 is testis-specific, indicating a potential role for hD55 in testis development and spermatogenesis.

Aging↗

PubMed1994

Developmental expression of testis messenger ribonucleic acids in the rat following propylthiouracil-induced neonatal hypothyroidism.

Propylthiouracil- (PTU) induced transient neonatal hypothyroidism increases adult rat testis weight 80-100%; this effect involves prolongation of Sertoli cell proliferation. To gain insight into developmental effects of PTU on the testis, we used Northern analysis to examine chronological expression of Sertoli cell mRNA in postnatal rat testes from rats that were untreated (controls) or were given PTU from birth to Day 25. Treated rats showed prolonged early expression of genes associated with dividing Sertoli cells such as MIS (Müllerian inhibiting substance) and c-erbA alpha (thyroid hormone receptor). Expression of several other Sertoli cell mRNAs (androgen-binding protein [ABP], clusterin, and inhibin-beta B) was delayed, as was that of hemiferrin, a spermatid-specific mRNA. Temporal expression patterns for other mRNAs (sulfated glycoprotein [SGP]-1, transferrin, and inhibin-alpha) were similar in control and treated animals. Additionally, thyroid hormone replacement in PTU-treated animals decreased MIS and c-erbA alpha mRNA expression to control levels. The altered developmental pattern of expression of a number of major Sertoli cell genes reflects a prolonged mitogenesis and delayed maturation of Sertoli cells in neonatally hypothyroid animals. Furthermore, our results suggest that thyroid hormone may directly potentiate molecular events associated with cessation of Sertoli cell proliferation and maturation during early testis development.

Animals↗

PubMed1977

Testis differentiation in the fetal and postnatal ferret.

Testis development has been examined in a series of 59 fetal and 9 postnatal ferrets from day 22 of the 40-42 day pregnancy, to 12 days after birth. Developing seminiferous tubules and interstitial cells were first seen on day 26, and were well established one day later. Differentiation was associated with cell enlargement and cell division, and consequently the testes grew distinctly more rapidly at this time than the corresponding ovaries. Up to the end of pregnancy the epithelioid interstitial cells, derived from stromal tissue, formed a large proportion of the testis. Lipid was distinguishable in them, histologically, from about day 30. As in various other mammals, there appeared to be some regression of the interstitial Leydig cells around the time of birth, when the seminiferous tubules resumed their growth. The intra-gonadal rete was present from day 22 onwards; it established connexions with the seminiferous tubules through the small tubuli recti by day 32.

Age Factors↗

PubMed2001

Testicular microlithiasis: is it a benign condition with malignant potential?

OBJECTIVE: To review the findings of testicular ultrasonography (US) in patients referred for testicular symptoms including pain, swelling and infertility, and to determine the prevalence of testicular microlithiasis (TM) and ist relevance to the development of testicular cancer. METHODS: Records of 3,026 patients referred for testicular US between 1994 and 1999 were evaluated. The indications for testicular US diagnosis, management and relevant histological details were obtained from medical records. Patients with TM had an annual sonographic follow-up unless they had testicular cancer, in which case follow-up repeat US with clinical reviews was more frequent. RESULTS: TM was found in 54 patients (1.77%; median age 34 years, range 12-83 years). The median follow-up was 36 months (range 12-18 months). Sixteen of these patients had testicular malignancy (30%). The remaining 38 patients had hydrocele and epididymal cysts (14), varicocele (7), epididymitis (2) and small testes (8), with 14 patients having no other pathology. One patient with a small testis developed a seminoma while under surveillance. Another patient with metastatic embryonal-cell carcinoma at initial diagnosis was found to have a seminoma 4 years following chemotherapy. The relative risk of testicular tumours in the presence of TM was 13.2 (confidence interval 8.3-21.5). CONCLUSION: TM can no longer be regarded simply as a benign condition because of its association with testicular malignancy. In our series, 2 patients (5.2%) developed interval testicular cancers during follow-up US. There is no convincing evidence to suggest that TM might be premalignant. In rare instances of radiologically indeterminate cases, biopsy of the testis may be necessary.

Adolescent↗

PubMed1993

A novel 205-kilodalton testis-specific serine/threonine protein kinase associated with microtubules of the spermatid manchette.

To identify proteins which interact with and potentially modulate the function of microtubules during spermatogenesis, we prepared a total testis MAP (microtubule-associated protein) antiserum and used it to isolate cDNA clones from a mouse testis cDNA expression library. Antibodies affinity purified by using one expression clone recognized a 205-kDa protein, termed MAST205, which colocalizes with the spermatid manchette. Sequencing of full-length cDNA clones encoding MAST205 revealed it to be a novel serine/threonine kinase with a catalytic domain related to those of the A and C families. The testis-specific MAST205 RNA increases in abundance during prepuberal testis development, peaking at the spermatid stage. The microtubule-binding region of MAST205 occupies a central region of the molecule including the kinase domain and sequences C terminal to this domain. Binding of MAST205 to microtubules requires interaction with other MAPs, since it does not bind to MAP-free tubulin. A 75-kDa protein associated with immunoprecipitates of MAST205 from extracts of both whole testis and testis microtubules becomes phosphorylated in in vitro kinase assays. This 75-kDa substrate of the MAST205 kinase may form part of the MAST205 protein complex which binds microtubules. The MAST205 protein complex may function to link the signal transduction pathway with the organization of manchette microtubules.

Amino Acid Sequence↗

PubMed2004

A targeted mutation of Nkd1 impairs mouse spermatogenesis.

Nkd1 is an antagonist of the canonical Wnt/beta-catenin signaling pathway. The EF-hand motif of Nkd1 is required for its inhibitory function. Early studies suggested that Nkd1 might play important roles in mouse embryonic development and tumorigenesis. We constructed Nkd1(-/-) mice whose Nkd1 protein lacked the EF-hand and was unable to inhibit Wnt/beta-catenin signaling. The homozygotes were viable and grew normally, but their fertility in males was reduced. In wild-type adult testes, Nkd1 mRNA was expressed more abundantly in the elongating spermatids than in the round spermatids. Lack of EF-hand caused reductions in the testis weight and sperm count by 30 and 60%, respectively. During testis development, Nkd1 mRNA expression started at the 25th day after birth, coincident with the onset of Wnt1 expression. Nuclear localization of beta-catenin increased in the elongating spermatids, suggesting that the mutant Nkd1 failed to inhibit the Wnt/beta-catenin pathway. These results suggest that deletion of the EF-hand from Nkd1 reduces the number of the elongating spermatids at haploid stage. In contrast, the mutant Nkd1 did not affect intestinal polyposis in Apc(Delta716) mice.

Adaptor Proteins, Signal Transducing↗

PubMed1988

Insulin-like growth factor I (IGF-I) receptors on Sertoli cells from immature rats and age-dependent testicular binding of IGF-I and insulin.

Insulin-like growth factor I (IGF-I) binding to cultured Sertoli cells from immature rats was quantitatively evaluated. The binding of 125I-IGF-I to the Sertoli cells was specific, time- and pH-dependent and reversible. Scatchard analysis yielded a Kd of 3.5 X 10(-9) M and a binding capacity of 2080 fmol/mg protein. Competition with IGF-I resulted in a half-maximal displacement by 2 nM IGF-I, whereas insulin up to a concentration of 100 nM gave virtually no displacement of IGF-I binding. Similarly, the gonadotropic hormones follitropin and lutropin did not compete with 125I-IGF-I binding. In previous studies, it was shown that cultured Sertoli cells from immature rats bind insulin with a Kd of 1.8 X 10(-9) M and a binding capacity of 8.5 fmol/mg protein. The binding of IGF-I and insulin to a total testis membrane fraction was studied using testes from immature and adult rats. In testis from 21-day-old rats, the maximal specific binding was relatively high for IGF-I (871 +/- 50 fmol/g wet weight) and relatively low for insulin (118 +/- 11 fmol/g wet weight). In adult testis, the maximal specific binding of IGF-I was 324 +/- 40 fmol/g wet weight and that of insulin was 330 +/- 17 fmol/g wet weight. The binding of IGF-I and insulin expressed as fmol bound per testis was increased 6-fold and 45-fold, respectively, between the age of 21 days and adult age. It is discussed that the numbers of receptors for IGF-I and insulin in testis may be developmentally regulated, and that IGF-I may be more important than insulin with respect to testis development and Sertoli cell maturation in the immature rat.

Aging↗

PubMed2002

Identification of human CDV-1R and mouse Cdv-1R, two novel proteins with putative signal peptides, especially highly expressed in testis and increased with the male sex maturation.

Human systemic carnitine deficiency (SCD) is a hereditary disease caused by the mutation of OCTN2 and has the characteristics of cardiac hypertrophy. Previous studies based on JVS mouse, an animal model of this disease, showed that Cdv-1 was highly expressed in ventricles of normal mouse, but was remarkably down-regulated in JVS mouse and can be up-regulated to normal level by breeding carnitine, which suggested Cdv-1 was possibly involved in cardiac hypertrophy caused by carnitine deficiency. In this study, the expression of human CDV-1, a homolog of mouse Cdv-1, was undetectable in heart by northern hybridization. The inconsistent expression levels of human CDV-1 and mouse Cdv-1 in heart implied that cardiac hypertrophy in human SCD might not be associated with the abnormal expression of CDV-1. Interestingly, another long transcripts of the gene, Cdv-1R/CDV-1R, were cloned in the present study, in mouse and human, respectively. This long transcript predominantly expressed in both human and mouse testis and its expression level was increased with testis development. Furthermore, we proved that the open reading frame of Cdv-1R/CDV-1R spans the exons 2 approximately 19 instead of exons 9 approximately 19; and the peptide encoded by CDV-1R was composed of 676 amino acids containing a putative signal peptide instead of 414 amino acids described previously. In addition, it was proved that the expression level of Cdv-1R in JVS mouse testis was as high as that in normal mouse testis, and both were not regulated by carnitine.

Alternative Splicing↗