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An integrase facilitates long-lasting foreign gene expression in vivo in mouse spermatogenic cells.

The objective of the present study was to attain long-lasting foreign gene expression in vivo in spermatogenic cells in the mouse testis for establishing spermatogenic-cell mediated gene transformation. Prior to in vivo gene transfer, surgical cryptorchidism was performed by retaining the testis into the abdominal cavity for 1 month to remove differentiated spermatogenic cells. Subsequently, in vivo gene transfer was conducted by electroporation with a lacZ reporter gene in combination with a retroviral integrase gene, and the testis was descended immediately to the scrotum to recover from the cryptorchidism, and restart spermatogenesis. At 1 month post-transfection in vivo, lacZ gene expression was detected in some spermatocyte-like cells in seminiferous tubules of the mouse testis. However, the recovery period of 1 month appeared to be too short, since no elongated and fully differentiated spermatids were found. At 2 months post-transfection, fully differentiated spermatogenic cells expressing the lacZ gene, albeit at low frequency, were detected when the integrase gene was co-transfected, while virtually no lacZ-positive cells were found in the absence of the integrase gene. It was concluded, therefore, that stable transformation of spermatogenic cells in vivo would be facilitated by integrase gene co-transfection.

Journal Article↗

Cloning and characterization of human haspin gene encoding haploid germ cell-specific nuclear protein kinase.

We report here the molecular cloning and characterization of human haspin cDNA and its genomic DNA construct. The haspin protein is a unique protein kinase, first isolated from mouse testis. Specifically expressed in mouse testicular germ cells, haspin is suggested to play a role in cell cycle arrest in haploid spermatids. Detection of human haspin by Northern blot analysis showed that the major transcript was 2.8 kilobases long and detected exclusively in the testis. The entire coding region of the human cDNA showed 68% identity with mouse haspin. The predicted amino acid sequence showed strong conservation of the kinase catalytic domain, leucine zipper, potential phosphorylation sites, and MEF2B homologous region, but a relatively unique N:-terminal region. Human haspin protein was also demonstrated to have protein kinase activity. The human haspin gene was mapped to chromosome 17p13 by computer database cloning of human genomic DNA. Furthermore, the genomic structure of human haspin was proven to be intronless and the whole transcription unit was found to be located in an intron of the integrin alphaE2 gene.

Amino Acid Sequence↗

Ethylnitrosourea treatment increases lectin binding to mouse germ cells.

Germ cell toxicity was assessed by investigating the binding of FITC-labeled lectins to mouse testis cells before and 18 days after treatment with ethylnitrosourea (ENU). Flow cytometry of testis cells dual-labeled with FITC-lectin plus the DNA stain, propidium iodide, allowed analysis of haploid (1C), diploid (2C), and dividing (4C) cell populations. Soybean agglutinin, wheat germ agglutinin, concanavalin A and Limax flavus agglutinin bound to normal mouse testis cells containing 1C, 2C or 4C DNA. Asparagus pea lectin and Bandeireae simplicifolia I isolectin B4 did not. ENU treatment reduced the number of testis cells and increased lectin binding, particularly of those lectins which bound to untreated cells.

Animals↗

Differential expression of opioid peptide genes by testicular germ cells and somatic cells.

Spermatogenic cells have been previously shown to be a major site of testicular proenkephalin gene expression. Using RNA gel-blot analysis of purified mouse and hamster germ cells and of testes from prepuberal and germ cell-deficient mutant mice, we now have demonstrated that, in addition to its previously described expression by somatic (Leydig) cells, the gene for a second opioid peptide precursor, pro-opiomelanocortin (POMC), is also expressed by spermatogenic cells. Of particular significance is the finding that the RNAs for proenkephalin and POMC are differentially regulated during spermatogenesis. Two forms of POMC RNA were detected in mouse testis, a larger component 675- to 750-nucleotides (nt) in size common to somatic and spermatogenic cells and a smaller 625-nt RNA found only in pachytene spermatocytes. Two distinct, cell-specific proenkephalin RNAs were also shown to be present in mouse testis: a 1700-nt transcript previously shown to be expressed by spermatogenic cells and a 1450-nt form associated with somatic cells. These data suggest that proenkephalin- and POMC-derived peptides are produced by both somatic cells and germ cells in the testis and in germ cells these two families of opioid peptides may function at different stages of spermatogenesis.

Animals↗

Hornet venom allergen antigen 5, Dol m 5: its T-cell epitopes in mice and its antigenic cross-reactivity with a mammalian testis protein.

BACKGROUND: A major venom allergen of white-faced hornet (Dolichovespula maculata) is antigen 5, Dol m 5. It is a 204-residue protein having 23% to 35% sequence identity with several proteins from diverse sources. The biologic function of antigen 5 and its sequence-related proteins is not known. OBJECTIVE: This study was done to delineate the T-cell epitopes of Dol m 5 and to test their cross-reactivity with a sequence-related mouse testis protein, tpx. METHODS: T-cell epitope mapping and cross-reactivity were studied with 15- or 20-residue peptides by their stimulation of spleen cells from mice immunized with recombinant Dol m 5 or tpx fragments. RESULTS: Three of 20 peptides studied were found to represent major T-cell epitopes of Dol m 5, being recognized by five or all of six mouse strains tested. One major epitope peptide, residue 176-195, showed cross-reactivity in BALB/c mice with the homologous antigen 5s from yellow jackets and wasps, as well as with mouse tpx. The cross-reactivity of Dol m 5 and mouse tpx is not reciprocal because spleen cells from tpx-immunized mice were stimulated by the hornet peptide, but cells from Dol m 5-immunized mice were not stimulated by the corresponding tpx peptides. CONCLUSION: Cross-reactivity of vespid antigen 5 and mouse tpx may be of importance in insect allergy because human and mouse testis proteins are highly homologous.

Allergens↗

In vivo role of alpha-mannosidase IIx: ineffective spermatogenesis resulting from targeted disruption of the Man2a2 in the mouse.

Alpha-mannosidase IIx (MX) is an enzyme closely related to the Golgi N-glycan processing enzyme alpha-mannosidase II (MII). The enzymatic activity of MX in vitro is minimal. Therefore, the in vivo role of MX in N-glycan processing is as yet unclear. The targeted disruption of the gene encoding MX in the mouse resulted in an obvious phenotype, i.e., MX-deficient males were found to be infertile. Testes from homozygous mutant male mice are smaller than those from wild-type or heterozygous littermates. Histology of the MX null mouse testis showed significant reduction of spermatogenic cells in the seminiferous tubules. Electron microscopy showed that prominent intercellular spaces surround MX-deficient spermatogenic cells, suggesting a failure of germ cell adhesion to Sertoli cells. Quantitative structural analyses of N-glycans from wild-type and MX-deficient mouse testis showed that wild-type testes contain GlcNAc-terminated complex type N-glycans, while they are significantly reduced in MX-deficient mutant testis. An in vitro assay for adhesion of spermatogenic cells to Sertoli cells was carried out. By testing the effect of each purified N-glycan oligosaccharide, it was demonstrated that a GlcNAc-terminated tri-antennary, fucosylated N-glycan has an activity on the adhesion between germ cells and Sertoli cells. Thus, the targeted disruption of the gene encoding MX uncovered a novel carbohydrate recognition system in a biologically important process, spermatogenesis.

Animals↗

Conservation and divergence of patterns of expression and lineage-specific transcripts in orthologues and paralogues of the mouse Hox-1.4 gene.

A possible correlation between the structural organization of homeobox-containing genes and their cell-specific expression was examined in studies determining similarities and differences in the expression patterns of orthologues and paralogues of the murine Hox-1.4 gene. We first compared the expression pattern of members of the Hox-1.4 subfamily, Hox-2.6 and Hox-4.2, in the adult mouse testis. Although these three evolutionarily related genes exhibited similar anterior limits of expression in the embryonic central nervous system, their cellular specificity of expression was very different in the adult testis. Hox-1.4 was abundantly expressed only in the germ cells; Hox-2.6 was expressed at very low levels in both spermatogenic cells and somatic cells; and Hox-4.2 transcripts appeared to be restricted to the somatic cells. We next analyzed the expression of several of the Hox-1.4 orthologues in the mouse testis to determine if other members of the Hox-1 cluster are involved in the male germ cell differentiation pathway. We showed that the two adjacent genes of Hox-1.4, Hox-1.3 and Hox-1.5, are expressed in the germ line but at lower levels. Further, both Hox-1.3 and Hox-1.4 produced unique, germ line-specific transcripts as compared to other adult tissues and the Day 12.5 embryo.

Animals↗

The critical region of overlap defining the AZFa male infertility interval of proximal Yq contains three transcribed sequences.

The position of deletion breakpoints in a series of four AZFa male infertility patients has been refined using new markers derived from BAC clone DNA sequence covering the AZFa male infertility interval. The proximal half of the AZFa interval is occupied by pseudogene sequences with homology to Xp22. The distal half contains an anonymous expressed sequence tag (named AZFaT1) found transcribed in brain, testis, and skeletal muscle and the DFFRY and DBY genes. All the patients have AZFaT1 and DFFRY deleted in their entirety and three patients additionally have DBY deleted. The three patients with AZFaT1, DFFRY, and DBY deleted show a severe Sertoli cell only syndrome type I phenotype, whereas the patient that has retained DBY shows a milder oligozoospermic phenotype. The expression of DBY in a cell line from this latter patient is unaltered; this shows that it is the loss of genes lying within the deletion that is responsible for the observed oligozoospermia. RT-PCR analysis of mouse testis RNA from normal and XXSxr(a) mice (devoid of germ cells) has shown that Dby is expressed primarily in somatic cells and that the level of expression is unaltered during germ cell differentiation. This contrasts with Dffry where no transcripts are detectable in XXSxr(a) mouse testis and expression occurs specifically in testis mRNA in a germ cell dependent fashion.

Adult↗

Molecular cloning and sequencing of sulfated glycoprotein-2 cDNA from testis of mouse: implications of two different mRNAs of SGP-2.

We cloned a mouse homolog of sulfated glycoprotein-2 (SGP-2) cDNA by screening a mouse testicular cDNA library and its nucleotide sequence was determined. The predicted amino acid sequence of the cDNA shares 93% identity with that of rat SGP-2. The nucleotide sequences of both cDNAs show extensive homology throughout the open reading frames and 3' untranslated regions. The 5' untranslated regions, however, share homology only up to 28 bp upstream from the start codons; the rest of sequences are quite different. DNA sequence homology search to mouse SGP-2 cDNA through the EMBL/GenBank database and a recent study on the genomic organization of rat TRPM-2 gene suggest a possibility that there are at least two different SGP-2 mRNAs as a result of alternative splicing and/or different promoter usage in mouse.

Alternative Splicing↗

Spermatogonial depletion in adult Pin1-deficient mice.

Spermatogonia in the mouse testis arise from early postnatal gonocytes that are derived from primordial germ cells (PGCs) during embryonic development. The proliferation, self-renewal, and differentiation of spermatogonial stem cells provide the basis for the continuing integrity of spermatogenesis. We previously reported that Pin1-deficient embryos had a profoundly reduced number of PGCs and that Pin1 was critical to ensure appropriate proliferation of PGCs. The current investigation aimed to elucidate the function of Pin1 in postnatal germ cell development by analyzing spermatogenesis in adult Pin1-/- mice. Although Pin1 was ubiquitously expressed in the adult testis, we found it to be most highly expressed in spermatogonia and Sertoli cells. Correspondingly, we show here that Pin1 plays an essential role in maintaining spermatogonia in the adult testis. Germ cells in postnatal Pin1-/- testis were able to initiate and complete spermatogenesis, culminated by production of mature spermatozoa. However, there was a progressive and age-dependent degeneration of the spermatogenic cells in Pin1-/- testis that led to complete germ cell loss by 14 mo of age. This depletion of germ cells was not due to increased cell apoptosis. Rather, detailed analysis of the seminiferous tubules using a germ cell-specific marker revealed that depletion of spermatogonia was the first step in the degenerative process and led to disruption of spermatogenesis, which resulted in eventual tubule degeneration. These results reveal that the presence of Pin1 is required to regulate proliferation and/or cell fate of undifferentiated spermatogonia in the adult mouse testis.

Age Factors↗

Germ cell apoptosis control during spermatogenesis.

The aim of the present study was to investigate the expression and role of c-Flip long isoform (c-FlipL), a known anti-apoptotic protein. No data are currently available on c-FlipL in male gonad before puberty; therefore, this study was carried out in prepuberal mouse testis. We investigated pachytene spermatocytes and spermatogonia by immunostaining of testis sections and found a strong and specific expression of c-FlipL in pachytene spermatocytes, while spermatogonia expressed very low levels of c-FlipL. This finding inversely correlated with the caspases activity, which was higher in spermatogonia as compared to pachytene spermatocytes. Other experiments carried out in an organ-culture model revealed that Fas-induced apoptosis was higher in spermatogonia as compared to pachytene spermatocytes. These data suggest that c-FlipL may play a role as an anti-apoptotic molecule in the prepuberal mouse testis and open new perspectives in the comprehension of the mechanisms controlling germ cells apoptosis.

Aging↗

Limb bud mesenchyme permits seminiferous cord formation in the mouse fetal testis but subsequent testosterone output is markedly affected by the sex of the donor stromal tissue.

Mesonephric stromal cells have previously been shown to migrate into the genital ridge and to be necessary for seminiferous cord formation in organ culture. Here, we asked whether there is a specific requirement for mesonephric stromal cells or whether another source of mesonephric stromal cells can be substituted. Hindlimb buds were immersed in a vital stain and then grafted to male gonad primordia and cultured for 96 hr. Immunocytochemical staining of laminin was used to identify seminiferous cord formation. For Sertoli and Leydig cell differentiation, müllerian inhibiting substance and delta 5-3 beta-hydroxysteroid dehydrogenase were used, respectively. Testosterone secreted into the culture medium was assessed by radioimmunoanalysis. It was found that hindlimb stromal cells, like mesonephric stromal cells, migrate into the genital ridge and allow seminiferous cord formation. These results indicate that mesonephric stromal cells are not specifically required for seminiferous cord formation in the mouse fetal gonad. Furthermore, although Sertoli and Leydig cells differentiate in the gonads grafted to hindlimbs from either male or female embryos, testosterone production was considerably higher with hindlimbs from males. A similar stromal sex effect on subsequent testosterone output was also seen with mesonephric stromal cells.

Animals↗

Relative biological effectiveness of 99mTc radiopharmaceuticals.

The radiotoxicity of three 99mTc-labeled compounds is investigated using spermatogenesis in mouse testis as the experimental model, and spermatogonial cell survival as the biological end point. The radiopharmaceuticals studied are pertechnetate (99mTcO4-), pyrophosphate (99mTc-PYP), and hydroxyethylene diphosphate (99mTc-HDP). The mean lethal doses at 37% survival (D37) are 0.70 +/- 0.06, 0.84 +/- 0.13, and 0.59 +/- 0.08 Gy for 99mTcO4-, 99mTc-PYP, and 99mTc-HDP, respectively. When these results are compared with the D37 value obtained with external x rays or internal gamma rays, the relative biological effectiveness (RBE) of these compounds are 0.94 +/- 0.09, 0.79 +/- 0.13, and 1.1 +/- 0.16, respectively. These results show that the radiotoxicity of 99mTc in mouse testis is essentially similar to that of low-LET radiations (i.e., RBE approximately 1). To understand these results, the distribution of these radiocompounds in the testis is determined and correlated with the observed RBE values. The expected range of RBE values for 99mTc radiopharmaceuticals in organs is 0.95 to 1.5, depending on the fraction of organ activity that is bound to DNA. This suggests that the Auger electrons emitted in the decay of 99mTc are not capable of causing extreme toxicity in vivo. These results provide further support for 99mTc as the radionuclide of choice for imaging in nuclear medicine.

Animals↗

Epitope analysis of a sperm acrosomal antigen defined by HSA-5 monoclonal antibody.

Among the monoclonal antibodies recommended by the WHO Sperm Antigen Workshop for immunocontraceptive vaccine development, HSA-5 showed a high degree of sperm specificity and significantly inhibited in vitro fertilization in both humans and mice. Using a Western blot assay, HSA-5 was found to recognize a sperm antigen designated as HSAg-5 (human) or MSAg-5 (mouse) which ranged in molecular weight from 18 to 100 kDa. This monoclonal antibody was used as the probe for the immunoscreening of mouse testis cDNA libraries constructed in the lambda gt-11 expression vector. One of the positive cDNA clones was shown to have a cDNA insert of approximately 1 kb and to encode a recombinant fusion protein containing 77 amino acid residues in the C-terminal region of MSAg-5. This 1 kb cDNA insert was engineered in a pGEX vector to express a recombinant glutathione S-transferase fusion protein (GST-5). Using an enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, both anti-GST-5 sera and the monoclonal antibody were shown to react with GST-5. The Northern blot of a mouse testis RNA preparation revealed that the isolated cDNA probe hybridized with a 4.0 kb mRNA. Several oligopeptides were synthesized based on the predicted C-terminal hydrophilic regions of the recombinant fusion protein. Using ELISA and a dot blot assay, peptide regions containing the immunogenic epitopes recognized by HSA-5 monoclonal antibody were identified.

Amino Acid Sequence↗

Translational regulation of the novel haploid-specific transcripts for the c-abl proto-oncogene and a member of the 70 kDa heat-shock protein gene family in the male germ line.

Expression of the c-abl proto-oncogene in the mouse testis is characterized by the production of a unique 4.7-kb transcript present in germ cells that have entered the haploid phase of spermatogenesis. A similar developmental stage specificity of expression is observed for a member of the 70-kDa heat-shock protein (hsp 70) gene family. A unique-sized hsp 70 transcript (T-hsp 70) is produced in haploid spermatids and is stable throughout spermatogenesis. In the present study, we examined the regulation of expression of these genes by examining their association with polyribosomes. The germ cell-specific c-abl and T-hsp 70 mRNA variants were both associated with the polysomal fractions of mouse testis cells, suggesting that they are functional mRNAs. However, both c-abl and T-hsp 70 mRNAs were also found in the ribonucleoprotein particle fractions. The distribution of these mRNAs in both the polysomal and nonpolysomal fractions is comparable to that seen for the mRNA of protamine-1, a gene whose expression in the testis is known to be regulated at the level of translation. In contrast, transcripts from the beta-tubulin gene were seen predominantly in the polyribosomal fractions. These findings suggest that translation of the novel c-abl and T-hsp 70 transcripts is confined to subpopulations of testicular cells.

Animals↗

Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways.

The immunopurification of the endogenous cytoplasmic murine histone deacetylase 6 (mHDAC6), a member of the class II HDACs, from mouse testis cytosolic extracts allowed the identification of two associated proteins. Both were mammalian homologues of yeast proteins known to interact with each other and involved in the ubiquitin signaling pathway: p97/VCP/Cdc48p, a homologue of yeast Cdc48p, and phospholipase A2-activating protein, a homologue of yeast UFD3 (ubiquitin fusion degradation protein 3). Moreover, in the C-terminal region of mHDAC6, a conserved zinc finger-containing domain named ZnF-UBP, also present in several ubiquitin-specific proteases, was discovered and was shown to mediate the specific binding of ubiquitin by mHDAC6. By using a ubiquitin pull-down approach, nine major ubiquitin-binding proteins were identified in mouse testis cytosolic extracts, and mHDAC6 was found to be one of them. All of these findings strongly suggest that mHDAC6 could be involved in the control of protein ubiquitination. The investigation of biochemical properties of the mHDAC6 complex in vitro further supported this hypothesis and clearly established a link between protein acetylation and protein ubiquitination.

Acetylation↗

Androgen down-regulated and region-specific expression of germ cell nuclear factor in mouse epididymis.

Germ cell nuclear factor (GCNF), a nuclear orphan receptor, involved in spermatogenesis, neurogenesis, differentiation, and embryo development, was highly expressed with two transcripts (7.4 and 2.3 kb) in mouse testis and with only one transcript (7.4 kb) slightly expressed in brain, liver, and kidney. The 2.3-kb transcript was restricted to round spermatids at stages VII and VIII of the spermatogenic cycle. The present report demonstrated its expression in epididymis as well, but at a very low level. Northern blot analysis showed two transcripts: a common 7.4-kb transcript and a unique 3.1-kb transcript. The expression levels of both GCNF transcripts in epididymis were down-regulated by androgen, as observed in castrated animals and aged mice. Polyclonal antisera against GCNF protein were raised. Western blot analysis showed the presence of only one band in total protein extracts from either mouse testis or epididymis. It indicated that the two mRNAs (7.4 and 3.1 kb) encode for the same protein as in testis. Fluorescent immunohistochemical staining and in situ hybridization showed that its expression was in the principal cell abundant in the corpus region. It implies that some androgen-regulated gene expressions located at the corpus principal cells might be controlled by GCNF.

3' Untranslated Regions↗