Meiotic Arrest and Germ Cell Apoptosis in Androgen-Binding Protein Transgenic Mice*

Selva, David M.; Tirado, Óscar M.; Torán, Núria; Suárez‐Quian, Carlos A.; Reventós, Jaume; Munell, Francina

doi:10.1210/endo.141.3.7383

Cited by 35 publications

(8 citation statements)

References 53 publications

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“…The results of this study confirm those of many earlier reports suggesting that both reduced [5,6,[8][9][10][11] and increased [18,[20][21][22][23] amounts of testicular ABP have deleterious effects on spermatogenesis.…”

Section: Discussionsupporting

confidence: 91%

“…Immunocytochemistry revealed intense ABP immunoreactivity in and around germ cells in all phases of development in the transgenic mice, and clusters of round spermatids showed intense immunoreactivity [20]. Selva et al [23] reported that meiotic arrest at the level of primary spermatocytes and apoptosis of growth-arrested germ cells were the causative factors for the decline of fertility seen in the ABPtransgenic (ABP-TG) mice.…”

Section: Introductionmentioning

confidence: 99%

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Dynamics of Testicular Germ Cell Proliferation in Normal Mice and Transgenic Mice Overexpressing Rat Androgen-Binding Protein: A Flow Cytometric Evaluation1

Jeyaraj

Grossman

Weaver

et al. 2002

Biology of Reproduction

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Transgenic mice carrying rat androgen-binding protein (ABP) genomic DNA express high amounts of testicular ABP and develop a progressive impairment of spermatogenesis. To understand the mechanism of these changes, we have studied the pattern of testicular germ cell proliferation from 7 to 360 days of age in wild-type (WT) control and transgenic homozygous (ABP-TG) mice by flow cytometry after labeling DNA in isolated germ cells with propidium iodide. At all ages studied, the body weight of the ABP-TG mice was lower than that of age-matched WT controls. Significantly reduced testicular weight and total germ cell number in the ABP-TG mice were evident from Day 30 and Day 60, respectively. Flow cytometric analysis of isolated germ cells revealed that the number of germ cells undergoing proliferation (S-phase cells) was identical in WT control and ABP-TG mice up to Day 14. Subsequently, the number of germ cells in S-phase was consistently higher in ABP-TG than in WT mice. The number of primary spermatocytes was significantly increased starting from Day 60, and the numbers of round and elongated spermatids were significantly reduced in the ABP-TG animals from Day 21 and Day 60 onwards, respectively. Immunocytometry for intracellular ABP at 90 days of age revealed that the percentage of ABP-containing germ cells was greater in ABP-TG than in WT mice. The continuous presence of ABP in mouse seminiferous tubules at greater than physiological concentrations facilitates the formation of primary spermatocytes but impairs subsequent transformation to round and elongated spermatids. Based on our observations and the analysis of the available literature, the most likely mechanism for production of these effects is sustained reduction in the bioavailability of androgens.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Dynamics of Testicular Germ Cell Proliferation in Normal Mice and Transgenic Mice Overexpressing Rat Androgen-Binding Protein: A Flow Cytometric Evaluation1

Jeyaraj

Grossman

Weaver

et al. 2002

Biology of Reproduction

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“…Previous studies have shown that the overexpression of a rat SHBG transgene in the Sertoli cells of the mouse testis results in an increase in germ cell apoptosis (18), but this does not occur in 11-kb human SHBG transgenic mice in which the transgene is expressed within the germ cells. Furthermore, there are marked differences in the levels of SHBG gene expression in the testis of mice and rats (33), and attempts to demonstrate that human Sertoli cells secrete a protein with steroid-binding properties similar to SHBG have not been successful (34).…”

Section: Discussionmentioning

confidence: 94%

“…The reaction was stopped by adding 25 mg/ml trypsin inhibitor, and the resulting solution was treated with deoxyribonuclease I (0.4 mg/ml) at room temperature for 5 min. The isolated tubules were subjected to several rounds of mincing and filtration, as described previously (17,18). After centrifugation, the pellet was resuspended in 15 ml of Dulbecco's modified Eagle's medium/NUT mix F-12 culture medium (Invitrogen) supplemented with 10% fetal bovine serum and incubated in a tissue culture flask for 5 h. The supernatant containing germ cells without Sertoli cells was recovered and centrifuged.…”

Section: Methodsmentioning

confidence: 99%

A Human Sex Hormone-binding Globulin Isoform Accumulates in the Acrosome during Spermatogenesis

Selva

Hogeveen²,

Seguchi

et al. 2002

Journal of Biological Chemistry

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Human sex hormone-binding globulin (SHBG) binds estradiol and testosterone with high affinity. Plasma SHBG is produced by hepatocytes, but the human SHBG gene is also expressed in the testis. Little is known about SHBG gene expression in the human testis, but human SHBG transcripts accumulate in a spermatogenic stagedependent manner in the testes of mice containing an 11-kb human SHBG transgene. We have now found that human SHBG transcripts containing an alternative exon 1 sequence are located specifically in the testicular germ cells of these transgenic mice, whereas murine SHBG transcripts are confined to Sertoli cells. In addition, we have detected immunoreactive human SHBG in the acrosome during all stages of spermiogenesis in mice containing an 11-kb human SHBG transgene. Western blots of germ cell extracts from these transgenic mice and from human sperm indicate that the immunoreactive human SHBG in the acrosome composes electrophoretic variants, which are 3-5 kDa smaller than the major electrophoretic isoforms of human SHBG in the blood. This apparent size difference is due in part to differences in glycosylation of plasma and acrosomal SHBG isoforms. The function of the human SHBG isoform in the acrosome is unknown, but it binds steroid ligands with high affinity. This is the first demonstration that human SHBG transcripts encode an SHBG isoform that remains within a cellular compartment.

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“…Testicular Cell Isolation and Primary Sertoli Cell Culture-Sertoli cells and germ cells were isolated from the testes of wild-type and transgenic mice using an established method (19,20) and frozen for RNA analysis (see below). For primary Sertoli cell cultures, a mixed population of Sertoli and germ cells was cultured at 33°C for 10 h in Dulbecco's modified Eagle's medium (Invitrogen) containing 2% fetal bovine serum, and germ cells were removed by washing and aspiration of the adhered Sertoli cells.…”

Section: Methodsmentioning

confidence: 99%

Repression of the Human Sex Hormone-binding Globulin Gene in Sertoli Cells by Upstream Stimulatory Transcription Factors

Selva

Hogeveen²,

Hammond

2005

Journal of Biological Chemistry

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Expression of the sex hormone-binding globulin gene (SHBG) in the liver produces SHBG, which transports sex steroids in the blood. In rodents, the SHBG gene is also expressed in Sertoli cells giving rise to the testicular androgen-binding protein, which is secreted into the seminiferous tubule where it presumably controls testosterone action. Evidence that the SHBG gene functions in this way in the human testis is lacking, and mice containing a human SHBG transgene (shbg4) under the control of its own promoter sequence are characterized by SHBG gene expression in the liver but not in the testis. A potential cis-element, defined as footprint 4 (FP4) within the human SHBG promoter, is absent in SHBG promoters of mammals that produce the testicular androgen-binding protein, and we have produced mice harboring a shbg4 transgene in which FP4 was deleted to evaluate its functional significance. Remarkably, these mice express the modified human SHBG transgene in the testis as well as the liver. Human SHBG transcripts were found within their Sertoli cells, primary cultures of which secrete human SHBG, and this was increased by treatment with follicle-stimulating hormone, retinoic acid, and estradiol but not testosterone. We have also found that the upstream stimulatory factors (USF-1 and USF-2) bind FP4 in vitro by electromobility shift assay of Sertoli cell nuclear extracts and in vivo by chromatin immunoprecipitation assay and conclude that USF transcription factors repress human SHBG transcription in Sertoli cells through an interaction with FP4 within its proximal promoter.

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Meiotic Arrest and Germ Cell Apoptosis in Androgen-Binding Protein Transgenic Mice*

Cited by 35 publications

References 53 publications

Dynamics of Testicular Germ Cell Proliferation in Normal Mice and Transgenic Mice Overexpressing Rat Androgen-Binding Protein: A Flow Cytometric Evaluation1

Dynamics of Testicular Germ Cell Proliferation in Normal Mice and Transgenic Mice Overexpressing Rat Androgen-Binding Protein: A Flow Cytometric Evaluation1

A Human Sex Hormone-binding Globulin Isoform Accumulates in the Acrosome during Spermatogenesis

Repression of the Human Sex Hormone-binding Globulin Gene in Sertoli Cells by Upstream Stimulatory Transcription Factors

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