The interaction of testicular androgen-receptor complex with rat germ cell and Sertoli cell chromatin.
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Animals↗
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Bilateral large cell calcifying Sertoli cell tumor of the testis in a 7-year-old boy.
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Calcinosis↗
Role of the basic helix-loop-helix protein ITF2 in the hormonal regulation of Sertoli cell differentiation.
Sertoli cells are a post-mitotic terminally differentiated cell population that forms the seminiferous tubules in the adult testis and provides the microenvironment and structural support for developing germ cells. During pubertal development, Sertoli cells are responsive to follicle-stimulating hormone (FSH) to promote the expression of differentiated gene products. The basic helix-loop-helix (bHLH) and inhibitors of differentiation (Id) transcription factors are involved in the differentiation of a variety of cell lineages during development. Both bHLH and Id transcription factors have been identified in Sertoli cells. A yeast two-hybrid screen was conducted using a rat Sertoli cell cDNA library to identify bHLH dimerization partners for the Id1 transcription factor. The ubiquitous bHLH protein ITF2 (i.e., E2-2) was identified as one of the interacting partners. The current study investigates the expression and function of ITF2 in Sertoli cells. ITF2 was found to be ubiquitously expressed in all testicular cell types including germ cells, peritubular myoid cells, and Sertoli cells. Stimulation of cultured Sertoli cells with FSH or dibutryl cAMP resulted in a transient decrease in expression of ITF2 mRNA levels followed by a rise in expression with FSH treatment. ITF2 expression was at its highest in mid-pubertal 20-day-old rat Sertoli cells. ITF2 was found to directly bind to negative acting Id HLH proteins and positive acting bHLH proteins such as scleraxis. Transient overexpression of ITF2 protein in cultured Sertoli cells stimulated transferrin promoter activity, which is a marker of Sertoli cell differentiation. Co-transfections of ITF2 and Id proteins sequestered the inhibitory effects of the Id family of proteins. Observations suggest ITF2 can enhance FSH actions through suppressing the inhibitory actions of the Id family of proteins and increasing the actions of stimulatory bHLH proteins (i.e., scleraxis) in Sertoli cells.
Animals↗
Histological and morphometric studies on the kinetics of germ cells and immature Sertoli cells during human prespermatogenesis.
Human prespermatogenesis between the 8th week of pregnancy and six months after birth was studied in testis material of 28 male foetuses from spontaneous abortions and 81 infants who died from sudden infant death. The foetuses and infants were grouped in 10 age groups. A first steep raise in the numbers of germ cells per 20 tubular cross sections from 22.3 in the first group up to 69.5 in group 3 was observed, i.e. up to the end of the 22nd week of pregnancy. Thereafter, a continuous decrease could be observed modulated by a second slighter increase during the first 4 months after birth. The ratio of germ cells and immature Sertoli cells improves from about 1:20 at the beginning to 1:8 in group 3; afterwards it changes in favour of the immature Sertoli cells down to 1:140 at the end of the study. The initial augmentation of germ cells is interpreted as the effect of a first proliferation wave comparable to that of M-prospermatogonia in other species. The decrease of germ cells is due to the stop of germ cell proliferation and simultaneous high proliferative activity of the immature Sertoli cells.
Abortion, Spontaneous↗
[Modulation of Leydig cell activity by Sertoli cell: an in vitro study].
In vivo studies indicate that FSH can modulate Leydig cells steroidogenic activity. However, in the testis only Sertoli cells contain specific FSH receptors. In order to clarify the mechanism by which FSH exerts this effect on testicular steroidogenesis, purified Pig Leydig and Sertoli cells were cultured alone or in co-culture. Leydig cell activity has been evaluated by two parameters: 1. hCG-stimulated testosterone secretion. 2. LH/hCG binding sites. FSH does not stimulate these two parameters of purified Leydig cells when cultured alone. On the other hand, when Leydig cells are co-cultured with Sertoli cells, FSH significantly increases these two parameters of Leydig cell function. These results suggest that the effect of FSH on Leydig cells is not direct but mediated by Sertoli cells.
Animals↗
Identification of IL-6 as one of the important cytokines responsible for the ability of mononuclear cells to stimulate Sertoli cell functions.
There is increasing evidence that locally produced cytokines may play an important role in the control of testicular function. In a previous report we demonstrated that medium conditioned by activated human peripheral blood mononuclear cells (PBMC-CM), which is a rich source of cytokines, has extremely potent effects on Sertoli cell transferrin and cGMP secretion. Part of this activity could be explained by interleukin-1beta (IL-1beta) but additional cytokines were evidently involved. In the present study we tried to characterize and purify additional components active on Sertoli cells from PBMC-CM. To this end PBMC-CM was subjected to a purification procedure involving successively: adsorption to silicic acid, affinity chromatography with an antiserum recognizing a mixture of cytokines except IL-1beta, gel-filtration, reversed-phase HPLC and cation-exchange FPLC. Throughout this protocol a Sertoli cell bioassay was used to monitor the effects on transferrin and cGMP production. After cation-exchange FPLC, SDS-PAGE using silver staining showed a single protein band in the bioactive fractions. NH2-terminal amino-acid sequencing revealed that the active principle(s) in this band corresponded to four truncated forms of IL-6 missing the first 13, 14, 17 and 18 N-terminal amino-acids, respectively. The truncated IL-6 molecules were as active as intact IL-6 in the Sertoli cell bioassay. Since neither IL-1beta nor IL-6 alone or in combination could account for the extremely potent effect of PBMC-CM, we tested a series of additional cytokines (IL-1alpha, INF-alpha, IL-4, TGF-beta, IFN-gamma) alone and in combination with IL-1beta and IL-6. These data suggest that IL-1beta, IL-6 and TNF-alpha display more than additive effects on Sertoli cell transferrin and cGMP secretion and that the combination of these cytokines may explain the major part of the effects observed with crude PBMC-CM. The observation that the latter effects could be observed with murine as well as human IL-1beta, IL-6 and TNF-alpha further supports the potential physiological relevance of these findings.
Amino Acid Sequence↗
Cytoplasmic granular change of Sertoli cells in two cases of Sertoli-cell-only syndrome.
The testicular biopsy specimens of two cases of Sertoli-cell-only syndrome are described, in which some of the Sertoli cells are filled with coarse cytoplasmic eosinophilic granules. Histochemical stains suggest that the granules contain glycocompounds and phospholipids. On electron microscopy, the granules prove to be densely populated secondary lysosomes, containing membrane fragments, phospholipid-like materials, and other amorphous masses of various densities. Whether the excessive secondary lysosomes arise as a result of some metabolic block in the Sertoli cells, or merely represent autophagy in response to the absence of germ cells, cannot be determined. A search of the literature indicates that this is the first instance, to our knowledge, in which such changes are reported in Sertoli-cell-only syndrome.
Adult↗
Mitotic activity of Sertoli cells in adult human testis: an immunohistochemical study to characterize Sertoli cells in testicular cords from patients showing testicular dysgenesis syndrome.
During puberty, normal somatic Sertoli cells undergo dramatic morphological changes due to the differentiation of immature pre-Sertoli cells in functionally active adult Sertoli cells. Sertoli cell maturation is accompanied with loss of their mitotic activity before onset of spermatogenesis and loss of pre-pubertal and occurrence of adult immunohistochemical Sertoli cell differentiation markers. Testes of infertile adult patients often exhibit numerous histological signs of testicular dysgenesis syndrome (TDS) such as microliths, Sertoli cell only (SCO) tubules, tubules containing carcinoma in situ and immature seminiferous tubules (Sertoli cell nodules). Sertoli cell tumours, however, are very rare neoplasms possibly due to the fact that the mechanism and temporal origin of neoplastic Sertoli cells underlying Sertoli cell tumourigenesis still remain unknown. To clarify the state of Sertoli cell differentiation in both immature seminiferous tubules of adult patients with TDS and Sertoli cell tumour, we compared the expression of the Sertoli cell differentiation markers vimentin, inhibin-alpha, anti-Muellerian-hormone, cytokeratin 18, M2A-antigen, androgen receptor and connexin43 with that of SCO tubules with hyperplasia. In addition, we demonstrated for the first time the existence of proliferating Sertoli cells by Ki67- and PCNA-immunostaining in Sertoli cell nodules of the adult human testis. Our data indicate that mitotically active Sertoli cells in Sertoli cell nodules will be arrested prior to puberty and, contrary to dogma, do not represent foetal or neonatal cells. Since all markers in Sertoli cell nodules revealed a staining pattern identical to that in neoplastic Sertoli cells, but different to that in Sertoli cells of SCO tubules with hyperplasia, it may be speculated that Sertoli cell tumours in adult men may originate from Sertoli cell nodules.
Adult↗
Hormonal regulation and differential actions of the helix-loop-helix transcriptional inhibitors of differentiation (Id1, Id2, Id3, and Id4) in Sertoli cells.
The testicular Sertoli cells support spermatogenesis by providing a microenvironment and structural support for the developing germ cells. Sertoli cell functions are regulated by the gonadotropin FSH. Sertoli cells become a terminally differentiated nongrowing cell population in the adult. In response to FSH, the Sertoli cells express a large number of differentiated gene products, such as transferrin, which transports iron to the developing germ cells. Previously, members of the basic helix-loop-helix (bHLH) family of transcription factors have been shown to influence FSH-mediated gene expression in Sertoli cells. The functions of the bHLH proteins are modulated by Id (inhibitor of differentiation) proteins, which lack the DNA-binding basic domain. The Id proteins form transcriptionally inactive dimers with bHLH proteins and thus regulate cell proliferation and differentiation. The current study investigated the expression and function of Id proteins in the postmitotic Sertoli cell. Freshly isolated and cultured Sertoli cells coexpress all four isoforms of Id (Id1, Id2, Id3, and Id4), as determined by immunoprecipitation with isoform-specific anti-Id antibodies, RT-PCR, and Northern blot analysis. Id2 and Id3 expression levels seem higher than Id1. Interestingly, the expression of Id4 in Sertoli cells is only detectable after stimulation with FSH or cAMP. The Id1 expression is down-regulated by FSH and cAMP, whereas Id2 and Id3 levels remain unchanged in response to FSH. In contrast, serum induces the expression of Id1, Id2, and Id3. Treatment of Sertoli cells with serum significantly reduces the expression of the larger 4-kb Id4 transcript and promotes the presence of a novel 1.3-kb transcript of Id4. The regulatory role of FSH in the expression of all four isoforms of Id is mimicked by a cAMP analog, suggesting that the actions of FSH are mediated through the protein kinase A pathway. An antisense approach was used to study the functional significance of Id proteins in Sertoli cells. Antisense to Id1 stimulated transferrin promoter activity in a transient transfection assay. Interestingly, an antisense to Id2 down-regulated transferrin promoter activity. Id3 and Id4 antisense oligonucleotides had no effect on FSH-mediated transferrin promoter activation. Contrary to the hypothesis that Id proteins have redundant functions, the results of the current study suggest that Id1, Id2, Id3, and Id4 are differentially regulated and may have distinct functions. Id1 may act to maintain Sertoli cell growth potential, whereas Id2 and Id4 may be involved in the differentiation and hormone regulation of Sertoli cells.
Animals↗
Modulation of Leydig cell functions by culture with Sertoli cells or with Sertoli cell-conditioned medium: effect of insulin, somatomedin-C and FSH.
The potential regulatory action of Sertoli cells on Leydig cell functions has been investigated by using a coculture system of Leydig and Sertoli cells obtained from immature pig or by culturing Leydig cells with Sertoli cell-conditioned medium (SCCM). Coculture of Leydig and Sertoli cells for 48 h in the absence of insulin or somatomedin-C (Sm-C), produced a small but significant increase in both hCG receptors and hCG-induced testosterone production. Addition to the medium of pFSH (100 ng/ml), insulin (5 micrograms/ml) or somatomedin-C (50 ng/ml) produced a marked increase in these two parameters of Leydig cell function. A further significant increase was observed when pFSH was associated with insulin or Sm-C. In contrast, coculture of Leydig cells with aortic endothelial cells decreased both the hCG receptor number and the hCG responsiveness. SCCM stimulated Leydig cell testosterone production following a 4 h incubation. The stimulation depended upon the amount of SCCM used and the conditions in which Sertoli cells were cultured. The most active was the medium from cells cultured in the presence of pFSH and insulin at high concentrations. Since pig Sertoli cells have specific somatomedin-C receptors, but not insulin receptors, it is likely that the effect of micromolar concentrations of insulin are exerted through Sm-C receptors. In addition, SCCM produced a long-term effect after 48 h incubation. SCCM from cells cultured in the absence of insulin and pFSH inhibited both the hCG receptor number and hCG responsiveness. A similar inhibition was observed with SCCM medium from cells cultured without insulin but with pFSH.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
FSH regulates cultured Leydig cell function via Sertoli cell proteins: an in vitro study.
The effects of follicular stimulating hormone (FSH) on testicular steroidogenic activity has been studied by testing the capacity of conditioned medium (CM) by both unstimulated (control) Sertoli cells (C-CM) and FSH stimulated Sertoli cells (FSH-CM) to influence porcine cultured Leydig cell activity. Leydig cells cultured in FSH-CM for 48 hrs, as compared to C-CM, show a significant (P less than 0.05) increase in [125I]-hCG binding (150% +/- 4) and hCG-stimulated testosterone (T) secretion (266% +/- 42). In addition, the stimulating effect of FSH-CM on Leydig cell function as compared to C-CM, is trypsin sensitive, non dialyzable, heat stable, acid resistant and is chromatographed following gel filtration (Sephadex G 100) into two different peaks of activity. These data suggest that FSH regulates Leydig cell function via (at least two types of) Sertoli cell secreted proteins.
Animals↗
The second messenger pathway for germ cell-mediated stimulation of Sertoli cells.
Treatment of cultured rat Sertoli cells with FSH or dibutyryl cAMP for 30 min resulted in phosphorylation of the same Sertoli cell proteins. Different Sertoli cell proteins were phosphorylated after calcium ionophore A23187 and 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. A23187 stimulated the phosphorylation of hsp27, while TPA alone had no effect. TPA plus A23187 resulted in phosphorylation of a 14 kDa protein, in addition to hsp27. The effect of TPA plus A23187 was identical to that of germ cells on Sertoli cell protein phosphorylation. FSH-stimulated cAMP production by Sertoli cells was reduced by prior exposure of Sertoli cells to germ cells. The results indicate that germ cells stimulate Sertoli cells by the inositol trisphosphate/diacylglycerol mediated second messenger pathway. The results also suggest that the germ cell-activated pathway interacts within Sertoli cells to modulate Sertoli cell response to FSH.
Animals↗
Expression and function of class B scavenger receptor type I on both apical and basolateral sides of the plasma membrane of polarized testicular Sertoli cells of the rat.
Class B scavenger receptor type I (SR-BI), a multiligand membrane protein, exists in various organs and cell types. In the testis, SR-BI is expressed in two somatic cell types: Leydig cells and Sertoli cells. Unlike interstitially localized Leydig cells, Sertoli cells present within the seminiferous tubules keep contact with spermatogenic cells and form the tight junction to divide the seminiferous epithelium into the basal and adluminal compartments. In this study, the expression and function of SR-BI in rat Sertoli cells were examined with respect to dependency on the spermatogenic cycle, the plasma membrane polarity, and the pituitary hormone follicle-stimulating hormone (FSH). When the expression of SR-BI was histochemically examined with testis sections, both protein and mRNA were already present in Sertoli cells during the first-round spermatogenesis and continued to be detectable thereafter. The level of SR-BI mRNA expression in Sertoli cells was lower at spermatogenic stages I-VI than at other stages. SR-BI was present and functional (in mediating cellular incorporation of lipids of high density lipoprotein) at both the apical and basolateral surfaces of polarized Sertoli cells. Finally, SR-BI expression at both the protein and mRNA levels was stimulated by FSH in cultured Sertoli cells. These results indicate that SR-BI functions on both the apical and basolateral plasma membranes of Sertoli cells, and that SR-BI expression in Sertoli cells changes during the spermatogenic cycle and is stimulated, at least in cultures, by FSH.
Animals↗
Three-dimensional reconstruction of a rat stage V Sertoli cell: II. Morphometry of Sertoli--Sertoli and Sertoli--germ-cell relationships.
Sertoli--Sertoli and Sertoli--germ-cell configurational relationships were studied using morphometric techniques and direct measurements as obtained from micrographs used to reconstruct a model of a rat stage V Sertoli cell. Regional areas of the Sertoli cell surface, which faced germ cells, other Sertoli cells, or noncellular structures, were expressed as relative surface area percentages; and the absolute surface areas for these regional areas were calculated. The surface areas of the reconstructed cell, in its unmagnified state, was found to be 12,163 micron2. Cell processes were enumerated and studied using morphometric techniques. The surface area of the reconstructed Sertoli cell facing germ cells and Sertoli cells was also determined. Five Sertoli cells showed extensive contact with the reconstructed cell at the level of the Sertoli--Sertoli junctional contact region. This contact region averaged 3.51 micron in width. The relative and absolute surface area of subsurface ectoplasmic specialization of the Sertoli cell that faced germ cells and other Sertoli cells was calculated, and the extent of penetration of step 17 spermatids into the Sertoli crypts was determined. Surface relationships of the reconstructed cell to cellular and noncellular elements were depicted on outline drawings of the Sertoli cell.
Animals↗
Creatine metabolism in the seminiferous epithelium of rats. II. Effect of modulators of cellular biochemical function on creatine secretion by cultured Sertoli cells.
The Sertoli cells have been identified as the primary locus for creatine synthesis within the seminiferous epithelium. The purpose of the studies reported here was to examine the effect of modulators of Sertoli cell function on creatine secretion by primary cultures of these cells. Sertoli cell-enriched cultures, maintained in a defined medium, secreted creatine into the incubation medium in a manner that was linear with time over at least 6 h, but which had reached a plateau within 24 h. Secretion was stimulated by physiological and toxicological modulators of Sertoli cell function. Incubation of Sertoli cell-enriched cultures in the presence of FSH (> or = 40 mU ml-1), dibutyryl cyclic AMP (> or = 0.1 mmol l-1), mono-(2-ethylhexyl) phthalate (> or = 1 mumol l-1) or cadmium (> or = 3 mumol l-1) increased the secretion of creatine into the incubation medium by at least 85% over 24 h. Creatine secretion by Sertoli cell-enriched cultures, incubated over 4 h in a balanced salt solution, was independent of exogenous L-glutamine. However, the stimulation of secretion induced by 1 mmol dibutyryl cyclic AMP l-1 was dependent on the presence of 4 mmol L-glutamine l-1 in the incubation medium, which suggests that an increase in creatine secretion occurs as a consequence of stimulated glutamine oxidation.
1-Methyl-3-isobutylxanthine↗
Modulation of MAA-induced apoptosis in male germ cells: role of Sertoli cell P/Q-type calcium channels.
Spontaneous germ cell death by apoptosis occurs during normal spermatogenesis in mammals and is thought to play a role in the physiological mechanism limiting the clonal expansion of such cell population in the male gonad. In the prepubertal rat testis, the most conspicuous dying cells are pachytene spermatocytes, which are also the primary target of the apoptosis experimentally induced by the methoxyacetic acid (MAA). Since we have recently reported that Sertoli cells, the somatic component of the seminiferous epithelium, regulate not only germ cell viability and differentiation but also their death, we have further investigated the mechanism involved in such a control. In this paper we have used the protein clusterin, produced by Sertoli cells and associated with tissue damage or injury, as indicator of germ cell apoptosis in rat seminiferous tubules treated with MAA in the presence or in the absence of omega-agatoxin, a specific inhibitor of P/Q type voltage-operated calcium channels (VOCC's). We performed both a qualitative analysis of clusterin content and germ cell apoptosis by immunofluorescence experiments and a quantitative analysis by in situ end labelling of apoptotic germ cells followed by flow cytometry. The results obtained demonstrate that Sertoli cells modulate germ cell apoptosis induced by methoxyacetic acid also throughout the P/Q-type VOCC's.
Acetates↗
The hormonal and cellular control of Sertoli cell secretion.
Sertoli cells synthesize and secrete a number of cell-specific products including androgen binding protein (ABP), as well as "serum proteins" such as transferrin. The secretion of these proteins is regulated by extra-testicular hormones such as FSH and insulin; Leydig cell-produced steroids and proopiomelano-cortin-derived peptides; and the presence of peritubular myoid cells and/or factors secreted by these cells. Many of the Sertoli cell proteins are secreted in a cyclic fashion during the different stages of the spermatogenic cycle suggesting communication between Sertoli cells and developing germ cells. The availability of quantitative measurements for Sertoli cell-specific proteins such as ABP make it feasible to follow Sertoli cell function in vivo by measuring these products in serum. A bidirectional secretion of proteins by Sertoli cells is proposed to explain the presence of specific peptides in the male reproductive tract and blood.
Androgen-Binding Protein↗
Comparative aspects of spermatogenic cell metabolism and Sertoli cell function in Xenopus laevis and mammals.
Due to the relative dearth of data regarding somatic cell-germ cell interactions in the testes of non-mammalian chordates, functional homologies between Sertoli cells from diverse organisms have been difficult to assess. However, recent developments in non-mammalian testis cell and organ culture techniques have provided experimental approaches to compare Sertoli cell-germ cell interactions in different vertebrates. Data from in vitro analyses of Sertoli cell-germ cell interactions are presented to suggest that Sertoli cells from rodents and the frog Xenopus laevis have similarities in supporting energy metabolism and glutathione metabolism in spermatogenic cells. Comparative in vitro analyses of Sertoli cell functions should provide further insights into the evolution of cell-cell interactions in the testes.
Animals↗