Mouse DCUN1D1 (SCCRO) is required for spermatogenetic individualization.

Squamous cell carcinoma-related oncogene (SCCRO, also known as DCUN1D1) is a component of the E3 for neddylation. As such, DCUN1D1 regulates the neddylation of cullin family members. Targeted inactivation of DCUN1D1 in mice results in male-specific infertility.

Increased proliferation but decreased steroidogenic capacity in Leydig cells from mice lacking cyclin-dependent kinase inhibitor 1B.

Proliferating cells express cyclins, cell cycle regulatory proteins that regulate the activity of cyclin-dependent kinases (CDKs). The actions of CDKs are regulated by specific inhibitors, the CDK inhibitors (CDKIs), which are comprised of the Cip/Kip and INK4 families. Expression of the Cip/Kip CDKI 1B (Cdkn1b, encoding protein CDKN1B, also called p27(kip1)) in developing Leydig cells (LCs) has been reported, but the function of CDKN1B in LCs is unclear.

Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero.

Exposures to di-(2-ethylhexyl) phthalate (DEHP) have been shown to be associated with decreased adult testosterone (T) levels and increased Leydig cell numbers. As yet, little is known about DEHP effects in utero on fetal Leydig cells (FLC). The present study investigated effects of DEHP on FLC function.

Phthalate ester toxicity in Leydig cells: developmental timing and dosage considerations.

Humans have significant exposures to phthalates, as these chemical plasticizers are ubiquitously present in flexible plastics. Recent epidemiological evidence indicates that boys born to women exposed to phthalates during pregnancy have an increased incidence of congenital genital malformations and spermatogenic dysfunction, signs of a condition referred to as testicular dysgenesis syndrome (TDS). TDS is thought to develop as a result of environmental factors that cause a testicular disturbance at an early fetal stage with a resultant spectrum of clinical testicular dysfunction, ranging from impaired spermatogenesis and genital malformations to increased risk for development of testicular cancer.

Activin B can signal through both ALK4 and ALK7 in gonadotrope cells.

Background: Activins stimulate pituitary FSH synthesis via transcriptional regulation of the FSHbeta subunit gene (Fshb). Like other members of the TGFbeta superfamily, these ligands signal through complexes of type I and type II receptor serine/threonine kinases. The type I receptors, or activin receptor-like kinases (ALKs), propagate intracellular signals upon ligand binding and phosphorylation by associated type II receptors.

Acute regulation of murine follicle-stimulating hormone beta subunit transcription by activin A.

In rodents, activins stimulate immediate-early increases in pituitary follicle-stimulating hormone beta (Fshb) subunit transcription. Here, we investigated the underlying signaling mechanisms using the mouse gonadotrope cell line, LbetaT2. Activin A increased mouse Fshb-luciferase reporter activity within 4 h through a Smad-dependent signaling pathway.

Rapid glucocorticoid mediation of suppressed testosterone biosynthesis in male mice subjected to immobilization stress.

Physical and psychosocial stress challenge homeostasis, increasing glucocorticoid secretion (in rodents, corticosterone [CORT]) while decreasing testosterone (T) levels. The dynamics of stress-induced changes in T, CORT, and luteinizing hormone (LH) concentrations in mice have not been investigated previously. In particular, it remains to be established whether there is a rapid effect of CORT that is directly mediated by glucocorticoid receptors (GRs) in the testis.

Müllerian-inhibiting substance inhibits rat Leydig cell regeneration after ethylene dimethanesulphonate ablation.

The postnatal development of Leydig cell precursors is postulated to be controlled by Sertoli cell secreted factors, which may have a determinative influence on Leydig cell number and function in sexually mature animals. One such hormone, Mullerian inhibiting substance (MIS), has been shown to inhibit DNA synthesis and steroidogenesis in primary Leydig cells and Leydig cell tumor lines. To further delineate the effects of MIS on Leydig cell proliferation and steroidogenesis, we employed the established ethylene dimethanesulphonate (EDS) model of Leydig cell regeneration.

Development of leydig cells in the insulin-like growth factor-I (igf-I) knockout mouse: effects of igf-I replacement and gonadotropic stimulation.

Targeted gene deletion of insulin-like growth factor-I (IGF-I) results in diminished numbers of Leydig cells (LCs) and lower circulating testosterone (T) levels in adult males. The impact of endogenous IGF-I withdrawal on proliferation (labeling index, LI) and differentiation of LCs was investigated, testing for restorative effects of IGF-I replacement and/or LH stimulation. With IGF-I replacement in mutant mice, LIs increased more than 200% (P < 0.

Cyclooxygenase 2 pathway mediates IL-1beta regulation of IL-1alpha, -1beta, and IL-6 mRNA levels in Leydig cell progenitors.

Prostanoids are arachidonic acid (AA) metabolites derived from the cyclooxygenase (COX1 and COX2 isozymes) pathway and are involved in signal transduction pathways activated by distinct ILs. Although COX1 is the constitutive isoform of COX, IL-1beta is a potent inducer of COX2 expression in distinct cell types. This study was designed to determine whether cyclooxygenases could mediate endogenous cytokine regulation in rat progenitor Leydig cells.

Identification of the oxidative 3alpha-hydroxysteroid dehydrogenase activity of rat Leydig cells as type II retinol dehydrogenase.

Dihydrotestosterone (DHT) is the most potent naturally occurring androgen, and its production in the testis may have important consequences in developmental and reproductive processes. In the rat testis, three factors can contribute to intracellular DHT levels: 1) synthesis of DHT from T by 5alpha-reductase, 2) conversion of DHT to 5alpha-androstane-3alpha, 17beta-diol (3alpha-DIOL) by the reductive activity of 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), and 3) conversion of 3alpha-DIOL by an oxidative 3alpha-HSD activity. While the type I 3alpha-HSD enzyme (3alpha-HSD1 or AKR1C9) is an oxidoreductase in vitro and could theoretically be responsible for factors 2 and 3, we have shown previously that rat Leydig cells have two 3alpha-HSD activities: a cytosolic NADP(H)- dependent activity, characteristic of 3alpha-HSD1, and a microsomal NAD(H)-dependent activity.

Potential regulation of membrane trafficking by estrogen receptor alpha via induction of rab11 in uterine glands during implantation.

The steroid hormone estrogen profoundly influences the early events in the uterus leading to embryo implantation. It is thought that estrogen triggers the expression of a unique set of genes in the preimplantation endometrium that in turn control implantation. To identify these estrogen-induced genes, we used a delayed implantation model system in which embryo attachment to endometrium is dependent on estrogen administration.

Progesterone induces calcitonin gene expression in human endometrium within the putative window of implantation.

The human endometrium acquires the ability to implant the developing embryo within a specific time window that is thought to open between days 19-24 of the secretory phase of the menstrual cycle. During this period the endometrium undergoes pronounced structural and functional changes induced by the ovarian steroids, estrogen and progesterone, that prepare it to be receptive to invasion by the embryo. The identification of reliable biochemical markers to assess this critical receptive phase in the context of the natural cycle remains one of the major challenges in the study of human reproduction.

Calcitonin is a progesterone-regulated marker that forecasts the receptive state of endometrium during implantation.

Previous studies established that in the rat, the uterus can accept a developing blastocyst for implantation only during a limited period of time on day 5 of gestation, termed the receptive phase. Our previous studies showed that the expression of calcitonin, a peptide hormone that regulates calcium homeostasis, is induced in rat uterus between days 3-5 of gestation and is switched off once the implantation process has progressed to day 6. In the present study, we analyze in detail how the expression of calcitonin messenger RNA (mRNA) in the uterus is regulated by the steroid hormones progesterone and estrogen and explore the possibility that calcitonin may serve as a potential marker of uterine receptivity.

A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor.

Synthetic steroid hormone antagonists are clinically important compounds that regulate physiological responses to steroid hormones. The antagonists bind to the hormone receptors, which are ligand-inducible transcription factors, and modulate their gene-regulatory activities. In most instances, a steroid receptor, such as progesterone receptor (PR) or estrogen receptor (ER), is transcriptionally inactive when complexed with an antagonist and competitively inhibits transactivation of a target steroid-responsive gene by the cognate hormone-occupied receptor.

Analysis of the functional role of steroid receptor coactivator-1 in ligand-induced transactivation by thyroid hormone receptor.

The nuclear hormone receptors belonging to the steroid/thyroid/retinoid receptor superfamily are ligand-inducible transcription factors. These receptors modulate transcription of specific cellular genes, either positively or negatively, by interacting with specific hormone response elements located near the target promoters. Recent studies indicated that the hormone- occupied, DNA-bound receptor acts in concert with a cellular coregulatory factor, termed coactivator, and the basal transcription machinery to mediate gene activation.

Ligand-dependent cross-talk between steroid and thyroid hormone receptors. Evidence for common transcriptional coactivator(s).

Steroid and thyroid hormone receptors exhibit striking structural and functional similarity, suggesting that these nuclear receptors may enhance transcription of target genes by similar mechanisms. To address this issue, we studied transcriptional interference between progesterone and thyroid hormone receptors in vivo and in vitro. We observed that transcriptional interference occurred in a ligand-dependent manner between progesterone receptor-B (PR-B) and thyroid hormone receptor (TR) alpha or beta in transient transfection experiments.

Transcriptional silencing by unliganded thyroid hormone receptor beta requires a soluble corepressor that interacts with the ligand-binding domain of the receptor.

Unliganded thyroid hormone receptor (TR) functions as a transcriptional repressor of genes bearing thyroid hormone response elements in their promoters. Binding of hormonal ligand to the receptor releases the transcriptional silencing and leads to gene activation. Previous studies showed that the silencing activity of TR is located within the C-terminal ligand-binding domain (LBD) of the receptor.