Paracrine-mediated apoptosis in reproductive tract development. (1/492)

In mammalian development, the signaling pathways that couple extracellular death signals with the apoptotic machinery are still poorly understood. We chose to examine Mullerian duct regression in the developing reproductive tract as a possible model of apoptosis during morphogenesis. The TGFbeta-like hormone, Mullerian inhibiting substance (MIS), initiates regression of the Mullerian duct or female reproductive tract anlagen; this event is essential for proper male sexual differentiation and occurs between embryonic days (E) 14 and 17 in the rat. Here, we show that apoptosis occurs during Mullerian duct regression in male embryos beginning at E15. Female Mullerian ducts exposed to MIS also exhibited prominent apoptosis within 13 h, which was blocked by a caspase inhibitor. In both males and females the MIS type-II receptor is expressed exclusively in the mesenchymal cell layer surrounding the duct, whereas apoptotic cells localize to the epithelium. In addition, tissue recombination experiments provide evidence that MIS does not act directly on the epithelium to induce apoptosis. Based on these data, we suggest that MIS triggers cell death by altering mesenchymal-epithelial interactions.  (+info)

Ptx1 regulates SF-1 activity by an interaction that mimics the role of the ligand-binding domain. (2/492)

Ptx1 (Pitx1) is a bicoid-related homeobox transcription factor expressed from the onset of pituitary development. It was shown to cooperate with cell-restricted factors, such as Pit1, NeuroD1/PanI and steroidogenic factor 1 (SF-1), to establish a combinatorial code conferring lineage- and promoter-specific gene transcription in the pituitary. Transcriptional synergism between Ptx1 and SF-1 on two SF-1 target genes, pituitary luteinizing hormone beta and Mullerian-inhibiting substance (MIS), requires SF-1 binding to DNA and appears to result from direct physical interaction between these two proteins. The interaction between the C-terminus of Ptx1 and the N-terminal half of SF-1 results in transcriptional enhancement that equals the activity of a constitutively active SF-1 mutant and that may mimic the effect of a still unidentified SF-1 ligand. Thus, the unmasking of SF-1 activity by Ptx1 may represent a developmental mechanism to alleviate the need for SF-1 ligand in transcription and, possibly, at critical times during organogenesis.  (+info)

Reversion of the differentiated phenotype and maturation block in Sertoli cells in pathological human testis. (3/492)

To study the relationship between abnormal Sertoli cell differentiation and spermatogenic impairment, we examined the expression of Sertoli cell markers normally lost at puberty, cytokeratin 18 (CK18), anti-Mullerian hormone (AMH) and M2A antigen, in three children (aged 1-2 years), 50 adults (aged 19-45 years) with obstructive or non-obstructive azoospermia or oligozoospermia, and six patients (aged 1-18 years) with 5 alpha-reductase deficiency. There was CK18 and/or AMH expression, but never M2A antigen expression, associated with spermatogonial arrest or Sertoli cell-only (SCO) syndrome in infertile men. Loss of M2A antigen suggests the transition of Sertoli cells to an adult phenotype, while CK18 and/or AMH expression may be a manifestation of de-differentiation of Sertoli cells. In 5 alpha-reductase deficiency, there was a sequential loss of CK18, M2A antigen and AMH around puberty, associated with partial spermatogenesis. The persistence of immature Sertoli cells expressing M2A antigen was associated with prepubertal seminiferous cords and SCO syndrome. Therefore, 5 alpha-reductase deficiency may prevent the maturation of Sertoli cells, resulting in impairment of spermatogenesis, and loss of M2A antigen expression coincides with a critical step in the Sertoli cell maturation. High follicle stimulating hormone concentrations due to failure of normal Sertoli cell differentiation indicate a normal development pattern of the hypothalamic-pituitary-gonadal axis.  (+info)

Anti-Mullerian hormone as a seminal marker for spermatogenesis in non-obstructive azoospermia. (4/492)

Anti-Mullerian hormone (AMH) also known as Mullerian inhibiting substance or factor, is a Sertoli cell-secreted glycoprotein responsible in male embryos for Mullerian duct regression. However, its role in adults remains unknown. AMH seminal concentrations have been evaluated using an enzyme-linked immunoassay in three groups of young men: group 1, fertile donors (n = 18); group 2, obstructive azoospermia (n = 9) after vasectomy or associated with deferent duct agenesia; and group 3, non-obstructive azoospermia with spermatogenesis deficiency and normal karyotype (n = 23). AMH was present in seminal plasma of most fertile donors at concentrations ranging from undetectable (<3.5 pmol/l) up to 543 pmol/l (geometric mean: 153 pmol/l), higher than the serum level (range <3.5 up to 67 pmol/l, geometric mean: 10.7 pmol/l, n = 13). Seminal AMH concentrations were undetectable in all obstructive azoospermic patients, confirming its testicular origin. In non-obstructive azoospermia (group 3), seminal AMH concentration was lower (range <3. 5-68.5 pmol/l, geometric mean: 17 pmol/l) than in fertile donors (P < 0.003) without correlation with plasma follicle stimulating hormone values. In group 3, comparison of seminal AMH concentration and the results of histological analysis of testicular biopsies revealed that undetectable AMH found in 14 cases was associated in 11 of them with lack of spermatozoa, while detectable concentrations of AMH (10-68.5 pmol/l) found in nine cases were associated in seven of them with persistent spermatogenesis. In the adult, AMH is secreted preferentially towards the seminiferous lumen. Although its relationship with spermatogenesis requires further investigation, our results suggest that seminal AMH may represent a non-invasive marker of persistent hypospermatogenesis in cases of non-obstructive azoospermia which may indicate the likely success of testicular spermatozoa recovery before intracytoplasmic sperm injection.  (+info)

Reverse transcription-polymerase chain reaction analysis of genes involved in gonadal differentiation in pigs. (5/492)

In mammals, testis development is initiated in the embryo as a response to the expression of the sex-determining gene, SRY. The time course of SRY expression during gonadal differentiation in the male has been described in detail only in mice and sheep. In this study, we used reverse transcription-polymerase chain reaction analysis to define the SRY transcription profile in pig genital ridges. SRY transcripts were first detectable from 23 days postcoitum (dpc), then declined sharply after 35 dpc. None were detected at 60 dpc. In addition, we analyzed temporal expression of other genes known to be involved in mammalian sex determination: WT-1, SF-1, SOX9, and AMH. A key stage seems to be 28 dpc, in which SOX9 expression switches between the male and female, and AMH expression begins to attest to Sertoli cell differentiation and to correspond to seminiferous cord formation in the male. Expression of gonadotropin receptors and aromatase was also investigated in porcine gonads, and we showed that their transcripts were detected very early on, especially in the male: 25 dpc for the LH receptor (rLH) and aromatase, and 28 dpc for the FSH receptor (rFSH). In the female, aromatase transcripts were not detected until 70 dpc, and rFSH expression occurred later: at 45 dpc at the onset of meiosis. Moreover, no difference was observed between the sexes for the onset of rLH transcription at 25 dpc. Such a thorough study has never been performed on pigs; developmental analysis will be useful for investigating sex-reversed gonads and determining ontogeny in intersexuality, a common pathology in pigs.  (+info)

Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. (6/492)

Mutations were introduced into conserved steroidogenic factor 1 (SF1)- and SOX9-binding sites within the endogenous mouse Mullerian inhibiting substance (Mis) promoter. Male mice homozygous for the mutant SF1-binding site correctly initiated Mis transcription in fetal testes, although at significantly reduced levels. Surprisingly, sufficient MIS was produced to eliminate the MUllerian ducts. In contrast, males homozygous for the mutant SOX9-binding site did not initiate Mis transcription, resulting in pseudohermaphrodites. These studies suggest an essential role for SOX9 in the initiation of Mis transcription, whereas SF1 appears to act as a quantitative regulator of Mis transcript levels, perhaps for influencing non-Mullerian duct tissues. Comparative studies of Mis expression in vertebrates indicate that the Mis promoter receives transcriptional inputs that vary between species but result in the same functional readout.  (+info)

Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS. (7/492)

Six human ovarian cancer cell lines and samples of ascites cells isolated from 27 patients with stage III or IV ovarian papillary serous cystadenocarcinoma were studied individually to test whether recombinant human Mullerian inhibiting substance (rhMIS) acts via its receptor. To do these experiments, we scaled up production of rhMIS and labeled it successfully with biotin for binding studies, cloned the human MIS type II receptor for mRNA detection, and raised antibodies to an extracellular domain peptide for protein detection. These probes were first tested on the human ovarian cancer cell lines and then applied to primary ovarian ascites cells. rhMIS inhibited colony growth of five of six cell lines that expressed the human MIS type II receptor mRNA by Northern analysis while not inhibiting receptor-negative COS cells. Flow cytometry performed on MIS-sensitive ovarian cancer cell lines demonstrated specific and saturable binding of rhMIS (Kd = 10.2 nM). Ascites cells from 15 of 27 or 56% of patients tested bound biotinylated MIS (MIS-biotin) and, of the 11 that grew in soft agarose, 9 of 11 or 82% showed statistically significant inhibition of colony formation. Of the 15 patients who bound biotinylated MIS, mRNA was available for analysis from 9, and 8 of 9 expressed MIS type II receptor mRNA by reverse transcription-PCR, showing a statistically significant correlation, compared with binding, by chi2 analysis (P = 0.025). Solid ovarian cancers were positive for the MIS type II receptor protein by immunohistochemical staining, which colocalized with staining for antibody to CA-125 (OC-125). Thus, the detection of the MIS type I receptor by flow cytometry may be a useful predictor of therapeutic response to MIS and may be a modality to rapidly choose patients with late-stage ovarian cancer for treatment with MIS.  (+info)

Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. (8/492)

Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alphabeta estrogen receptor knockout (alphabetaERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alphabetaERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Mullerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.  (+info)

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