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PubMed2000

Transient expression of activin betaA mRNA on osteoprogenitor cells in rat bone regeneration after drill-hole injury.

We investigated the expression of activin betaA on osteoprogenitor cells in the regenerating bone and bone marrow of the rat femur after drill-hole injury, by immunocytochemistry and in situ hybridization. The periosteum and endosteum adjacent to the wound region showed marked thickening at day 3 and abundant osteoprogenitor cells, which were immunoreactive for proliferating cell nuclear antigen and showed positive reactions for alkaline phosphatase activity, and existed in the inner layer of the periosteum as well as in the endosteum. During the same period, these osteoprogenitor cells began to exhibit activin betaA immunoreactivity and mRNA expression. However, the latter expression gradually reduced the intensity as the cells started to express osteocalcin mRNA during their differentiation to osteoblasts participating in the periosteal and medullary bone formation from day 5. Immunoreactivity for activin type IB and II receptors was also found on activin betaA-immunoreactive cells between days 3 and 7. The above findings suggest that proliferating osteoprogenitor cells, before their transformation to osteoblasts, transiently produce and release activin A, which may play crucial roles in bone and bone marrow regeneration in a receptor-mediated, autocrine and paracrine fashion.

Animals↗
PubMed2000

Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions.

The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function.

Activins↗
PubMed2001

In vitro secretion of FSH by cultured clinically nonfunctioning and gonadotroph pituitary adenomas is directly correlated with locally produced levels of activin A.

OBJECTIVE: Expression of mRNAs encoding activin and its antagonists inhibin and follistatin has been described in human pituitary adenomas, including clinically nonfunctioning adenomas (NFAs) and gonadotroph adenomas (Gn-omas). Since many of the NFAs and Gn-omas secrete FSH in vitro, we hypothesized that locally produced activin may stimulate secretion of FSH in these pituitary adenomas. PATIENTS AND METHODS: Pituitary adenoma tissue was obtained from 38 patients diagnosed preoperatively as having NFAs (n = 17), Gn-omas (n = 5), prolactinomas (n = 6) or growth hormone (GH)-producing adenomas (n = 10). Actual protein levels of activin, inhibin, follistatin, FSH and LH were measured in media of these 38 cultured pituitary adenomas. In addition, we investigated correlations between concentrations of these growth factors and hormones in NFAs and Gn-omas. RESULTS: Gn-omas were found to secrete significantly more activin A in their culture medium than PRL- and GH-producing adenomas (P < 0.05). Inhibin A and inhibin B protein levels in culture media were very low. A positive correlation between levels of activin A and FSH (r = 0.56, P < 0.005) was found, while no correlation between activin A and LH could be detected. Furthermore, levels of follistatin were positively correlated with activin A levels (r = 0.73, P < 0.0005). Comparison of the activin A:follistatin ratio with the measured FSH protein levels showed an even stronger relationship (r = 0.79, P < 0.0005). CONCLUSIONS: It is concluded that levels of activin A, follistatin and FSH in media of cultured nonfunctioning adenomas and gonadotroph adenomas are positively correlated. This suggests that these adenomas secrete FSH in response to the relatively high locally produced levels of activin A.

Activins↗
PubMed2001

Smad7 is induced by norepinephrine and protects rat hepatocytes from activin A-induced growth inhibition.

Activin A induces growth arrest of rat hepatocytes in vitro and in vivo. The alpha(1)-adrenergic agonist, norepinephrine (NE), enhances epidermal growth factor-stimulated DNA synthesis and inhibits activin A-induced growth inhibition, but the mechanisms of these actions are unclear. Smad proteins have recently been identified as intracellular signaling mediators of transforming growth factor-beta family members. In the present study, we explored how NE modulates the Smad signaling pathway in rat cultured hepatocytes. We demonstrate that NE inhibits activin A-induced nuclear accumulation of Smad2/3 and that NE rapidly induces inhibitory Smad7 mRNA expression. Infection of Smad7 adenovirus into rat hepatocytes inhibited activin A-induced nuclear accumulation of Smad2/3, enhanced epidermal growth factor-stimulated DNA synthesis, and abolished the growth inhibitory effect of activin A. We also demonstrated that the induction of Smad7 by NE is dependent on nuclear factor-kappa B (NF-kappa B). The amount of active NF-kappa B complex rapidly increased after NE treatment. Preincubation of the cells with an NF-kappa B pathway inhibitor N-tosyl-l-phenylalanine chloromethyl ketone or infection of the cells with an adenovirus expressing an I kappa B super-repressor (Ad5I kappa B) abolished the NE-induced Smad7 expression. These results indicate a mechanism of transmodulation between the Smad and trimeric G protein signaling pathways in rat hepatocytes.

Activins↗
PubMed2001

Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome.

Familial polycystic ovarian syndrome (PCOS) has been proposed to be linked to a site near the follistatin gene. We studied the concentrations of circulating follistatin, activin A and inhibin B in well-characterized subjects with PCOS (n = 108) and controls without PCOS (n = 20). Mean (+/- SEM) concentrations of follistatin were higher (P < 0.05) in PCOS (0.27 +/- 0.03 ng/ml) than controls (0.15 +/- 0.02 ng/ml) and activin A were lower (P < 0.05) in PCOS (0.20 +/- 0.01ng/ml) than controls (0.24 +/- 0.02 ng/ml). Inhibin B concentrations were not different between the two groups: PCOS (0.06 +/- 0.01ng/ml), and controls (0.06 +/- 0.01ng/ml). It is proposed that higher concentrations of follistatin with lower concentrations of activin A may relate to follicular development not proceeding beyond 8-10 mm and may be partly responsible for the lack of pre-ovular follicle development in PCOS.

Activins↗
PubMedDate not supplied

Linkage mapping of the ovine alpha-inhibin (INHA) beta(A)-inhibin/activin (INHBA) and beta(B)-inhibin/activin (INHBB) genes.

A full-sib mapping population was typed for Taql Southern blot RFLPs at the ovine alpha-inhibin (INHA), beta(A)-inhibin/activin (INHBA), and beta(B)-inhibin/activin (INHBB) loci. The most likely positions were found by genetic linkage analysis. INHA was placed on ovine chromosome 2q, between microsatellite markers BM6444 and INRA135, while INHBB was located 39 cM proximal to INHA between markers BMS1126 and BMS2626. The INHBA gene, a comparative mapping anchor locus, mapped to chromosome 4, between microsatellites OARCP26 and BMS719. These data confirm and refine previous chromosomal assignments by in situ hybridization, provide comparative mapping information, and identify microsatellite markers suitable for QTL association studies with inhibin/activin genes in ruminants.

Activins↗
PubMed1989

Possible involvement of inhibin in altered follicle-stimulating hormone (FSH) secretion during dissociated luteinizing hormone (LH) and FSH release: unilateral castration and experimental cryptorchidism.

Male rats were either unilaterally or bilaterally castrated, or were rendered cryptorchid when they were either 15 or 45 days old. Subsequently, blood was sampled over the next several weeks and plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and immunoreactive inhibin-alpha (irI alpha) levels were measured by specific radioimmunoassays (RIAs). At the end of the experiment, gonadal expression of inhibin-alpha, inhibin-beta A, and inhibin-beta B subunits was measured by S1 nuclease analysis and in situ hybridization. In both age groups, bilateral castration (BC) produced the expected marked (p less than or equal to 0.01) increases in plasma LH and FSH levels, and concomitant decreases in T and irI alpha secretion within 1 - 2 days after surgery. In 15-day-old animals, unilateral castration (UC) significantly increased FSH and decreased circulating levels of irI alpha, but did not measurably alter LH or androgen production. At 7 days after surgery, the level of inhibin mRNA in the remaining testis was unchanged. In 45-day-old animals, UC caused a measurable increase in FSH, with little or no changes in the circulating levels of irI alpha. Plasma T levels were lowered (p less than or equal to 0.05) by UC; however, there were no statistical changes in LH levels in these UC rats. Finally, T administration markedly reversed UC-induced increase in FSH secretion in both age groups. Androgen therapy also interfered with inhibin release in 45-day-old, but not in 15-day-old rats. In rats 15 days old at the time of surgery, cryptorchidism produced a small but measurable increase (p less than or equal to 0.05) in LH release at Week 6 only, which was accompanied by a significant (p less than or equal to 0.01) decline in T secretion. Plasma FSH levels were elevated at all times in cryptorchid rats, and at 2, 4, and 6 wk, these levels were not statistically distinguishable (p greater than 0.05) from those of castrated animals. In this group of rats, cryptorchidism caused a transient increase (p less than or equal to 0.05) in irI alpha values 1 wk after surgery, but no changes at later times. Finally, measurement of testicular inhibin-alpha subunit messenger RNA (mRNA) levels showed an approximately 2-fold increase compared to total RNA levels in the testis. However, because of the significant decrease in total RNA levels per testis caused by cryptorchidism, the absolute change in inhibin-alpha subunit mRNA levels per testis corresponded to an approximately 3-fold decrease.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Effect of activin A on in vitro development of rat preantral follicles and localization of activin A and activin receptor II.

Preantral follicles (140-160 microm) were isolated mechanically from the ovaries of 10-day-old rats and cultured in groups of four to six for 6 days in medium containing 0, 1, 10, or 100 ng/ml of activin A. Activin stimulated (P < 0.05) the growth of preantral follicles in a dose-dependent fashion and enhanced the proliferation of preantral, oocyte-free follicular cells. Furthermore, treatment with activin induced the majority of follicles to form an antrum-like structure and helped to maintain the ultrastructure of these follicles during culture. Activin A also induced further changes characteristic of follicle and oocyte maturation, such as the elongation of granulosa cells contacting the oocyte and migration of the cortical granules to the oocyte cortex. In addition, gene expression for activin and activin receptor type II (ActR II) was demonstrated in both the oocytes and the somatic cells using the reverse transcription-polymerase chain reaction, and immunohistochemical studies demonstrated the presence of activin and ActR II proteins in the somatic tissue and, especially, the oocytes of these follicles. It is concluded that, in vitro, activin A stimulates the growth of rat preantral follicles and promotes antrum formation. Furthermore, because activin A and ActR II are synthesized within preantral follicles, intrafollicular activin likely plays an important role in early follicular development.

Activin Receptors, Type II↗
PubMed2001

Interactions between follicle-stimulating hormone and growth factors in modulating secretion of steroids and inhibin-related peptides by nonluteinized bovine granulosa cells.

The aim was to investigate potential interactions between FSH and intraovarian growth factors in modulating secretion of inhibin A (inh A), activin A (act A), follistatin (FS), estradiol (E2), and progesterone (P4) by bovine granulosa cells cultured under conditions in which a nonluteinized FSH-responsive phenotype is maintained. Cells from 4- to 6-mm follicles were cultured in serum-free medium containing insulin (10 ng/ml) and androstenedione (10(-7) M), and effects of ovine FSH (0.037-3 ng/ml) were tested alone and in combination with insulin-like growth factors (IGF) (LR3 IGF-I analogue; 2-50 ng/ml) and epidermal growth factor (EGF; 0.1-10 ng/ml). Medium was changed every 48 h and cultures ended after 144 h, when cell number was determined. Between 48-96 h and 96-144 h, FSH promoted (P < 0.0001) increases in output of inh A (6-fold), act A (15-fold), FS (6-fold), and E2 (18-fold), with maximal responses (in parentheses) elicited by 0.33 ng/ml FSH during the final period. Higher FSH doses (1 and 3 ng/ml) gave reduced responses for each of the above hormones, whereas P(4) output was maximal (3-fold) at these doses. FSH promoted a slight increase in cell number ( approximately 1.7-fold; P < 0.001). LR3 IGF-I alone markedly increased (P < 0.0001) output of inh A (8-fold), act A (41-fold), FS (12-fold), and E2 (18-fold); this was accompanied by modest increases (P < 0.01) in P4 output ( approximately 2.5-fold) and cell number ( approximately 2-fold). Whereas FSH enhanced inh A, act A, FS, and E2 secretion evoked by lower doses of LR3 IGF-I, it suppressed (P < 0.001) the response to the highest dose. EGF alone promoted a 1.7-fold increase in cell number (P < 0.001) without affecting hormone release; however, it abolished (P < 0.001) FSH-induced secretion of inh A, act A, FS, and E2. Both FSH alone and LR3 IGF-I alone dose-dependently increased the act A:FS ratio ( approximately 3-fold; P < 0.005) and act A:inh A ratio (3-fold to 6-fold; P < 0.001), suggesting that both factors selectively raise activin "tone" and that this could be a key requirement for FSH and IGF-induction of follicular E2 production. This hypothesis was reinforced by the finding that addition of FS, to reduce the act A:FS ratio and sequester secreted activin, markedly suppressed (P < 0.001) FSH (3-fold)-, and LR3 IGF-I (2-fold)-induced E2 output.

Activins↗
PubMed1997

Focal brain injury increases activin betaA mRNA expression in hippocampal neurons.

The role of activin in the mammalian brain is of increasing interest as evidence accumulates to suggest a number of different neural functions. Here, we report that activin betaA mRNA is transiently induced in dentate gyrus neurons after unilateral mechanical brain injury by saline injection. Expression is dependent on NMDA receptor activation since pretreatment with MK801 (5 mg/kg, i.p.) largely attenuates the signal. Induction also requires de novo protein synthesis, as cycloheximide (10 mg/kg, i.p.) pretreatment abolishes the expression of activin betaA mRNA 1 h after injury. These results show that activin betaA mRNA expression is regulated by excitatory activity induced by focal brain injury and suggests a possible neuroplastic role in the recovery from such injury.

Animals↗
PubMed1998

Activin is an essential early mesenchymal signal in tooth development that is required for patterning of the murine dentition.

Development of the mammalian tooth has been intensively studied as a model system for epithelial/mesenchymal interactions during organogenesis, and progress has been made in identifying key molecules involved in this signaling. We show that activin betaA is expressed in presumptive tooth-germ mesenchyme and is thus a candidate for a signaling molecule in tooth development. Analysis of tooth development in activin betaA mutant embryos shows that incisor and mandibular molar teeth fail to develop beyond the bud stage. Activin betaA is thus an essential component of tooth development. Development of maxillary molars, however, is unaffected in the mutants. Using tissue recombination experiments we show that activin is required in the mesenchyme prior to bud formation and that although activin signaling from mesenchyme to epithelium takes place, mutant epithelium retains its ability to support tooth development. Implantation of beads soaked in activin A, into developing mandibles, is able to completely rescue tooth development from E11.5, but not E12.5 or E13.5, confirming that activin is an early, essential mesenchyme signal required before tooth bud formation. Normal development of maxillary molars in the absence of activin shows a position specific role for this pathway in development of dentition. Functional redundancy with activin B or other TGFbeta family members that bind to activin receptors cannot explain development of maxillary molars in the mutants since the activin-signaling pathway appears not to be active in these tooth germs. The early requirement for activin signaling in the mesenchyme in incisor and mandibular molar tooth germs must be carried-out in maxillary molar mesenchyme by other independent signaling pathways.

Activins↗
PubMed2000

Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in humanprostate and evidence for formation of new activin heterodimers of beta(C)-subunit.

Activin ligands are formed by dimerization of activin ss(A)- and/or ss(B)-subunits to produce activins A, AB, or B. These ligands are members of the transforming growth factor-ss superfamily and act as growth and differentiation factors in many cells and tissues. New additions to this family include activin ss(C)-, ss(D)-, and ss(E)-subunits. The aim of this investigation was to examine the localization of and dimerization among activin subunits; the results demonstrate that activin ss(C) can form dimers with activin ss(A) and ss(B) in vitro, but not with the inhibin alpha-subunit. Using a specific antibody, activin ss(C) protein was localized to human liver and prostate and colocalized with ss(A)- and ss(B)-subunits to specific cell types in benign and malignant prostate tissues. Activin C did not alter DNA synthesis of the prostate tumor cell line, LNCaP, or the liver tumor cell line, HepG2, in vitro when added alone or with activin A. Therefore, the capacity to form novel activin heterodimers (but not inhibin C) resides in the human liver and prostate. Activin A, AB, and B have diverse actions in many tissues, including liver and prostate, but there is no known biological activity for activin C. Thus, the evidence of formation of activin AC or BC heterodimers may have significant implications in the regulation of levels and/or biological activity of other activins in these tissues.

Activins↗
PubMed1996

Characterization and determination of the biological activities of noncleavable high molecular weight forms of inhibin A and activin A.

Recombinant expression of human alpha- and beta A-inhibin subunit cDNAs in mammalian 293 cells results in the secretion of 20-53K free alpha-subunit-derived products, 30-105K alpha beta A-inhibin dimers, and 24-110K beta A-activin dimers. The present study verifies that the wide variation in the size of these products is due to incomplete cleavage of the proteolytic processing sites and the differential glycosylation of the N-linked glycosylation site at amino acid number 302 in the alpha C-subunit. The identity of each of these products was established by mutagenesis of proteolytic processing sites and N-linked glycosylation sites, combined with the analysis of transfection products by immunoprecipitation and one- and two-dimensional SDS-PAGE (SDS/SDS-beta-ME). Transient expression of processing site mutants of the alpha- and beta A-subunits in 293 cells was used to generate microgram quantities of noncleavable 55K and 65K inhibin dimers, and noncleavable 110K activin A dimers. The 55K and 65K inhibin A forms were purified and found to be fully biologically active in a rat pituitary cell bioassay. The 110K high molecular weight (HMW) form of human activin A failed to show any FSH-releasing activity in the pituitary assay. Since radioactively labeled 55K and 65K inhibin A and 110K activin A remained intact after incubation with rat pituitary cells for 72 h, there appears to be no conversion of these dimers to lower molecular weight forms by proteolytic cleavage at additional sites. These results show for the first time that 55K and 65K inhibit A are intrinsically biologically active and do not require cleavage to the 32K form for activation. In contrast, cleavage of the 110K activin A precursor to the 24K form would appear to be necessary for activity.

Activins↗
PubMed2001

[Expression of inhibin alpha and inhibin/activin beta A subunits in the developing follicles of the duck].

The very sensitive quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to investigate the expression of mRNA for the inhibin alpha and inhibin/activin beta A subunit in the developing ovarian follicles of the duck. The results indicated all follicles showed the expression of mRNA for the inhibin alpha and inhibin/activin beta A. The inhibin alpha subunit mRNA is expressed more abundantly than the beta A subunit in the large preovulatory follicles. Competitive RT-PCR revealed that the expression of inhibin alpha subunit is the highest in small yellow follicles (SYF), the mean relative content for the F1, F2, F3, F4/5 and LWF (large white follicle) was 0.26 +/- 0.05, 0.28 +/- 0.07, 0.57 +/- 0.12, 0.98 +/- 0.09 and 0.026 +/- 0.006, respectively, compared to a mean relative content of 1.00 for the SYF. The highest level of inhibin/activin beta A mRNA was found in the F1 follicle, the mean relative content for the F2, F3, F4/5, SYF and LWF was 0.218 +/- 0.09, 0.111 +/- 0.03, 0.058 +/- 0.011, 0.053 +/- 0.013 and 0.005 +/- 0.002, respectively, compared to a mean relative content of 1.00 for the F1 follicle. Our data suggest that the expression of the alpha subunit is reduced with follicular development whereas beta A subunit expression is dramatically enhanced, which indicates the expression of inhibin alpha and inhibin/activin beta A subunit is differentially regulated during follicular development. In addition, the highest level of beta A mRNA in F1 follicle indicates the production of dimeric inhibin and/or activin primarily occurred in the largest F1 follicle.

Animals↗
PubMedDate not supplied

[Inhibin B immunocytochemistry for the prognosis assessment of undescended testis damage in children].

Inhibin B immunocytochemistry of both the alpha- and beta-subunits was studied in testicular biopsies from 18 prepubertal and postpubertal patients, with unilateral or bilateral cryptorchism. The present investigation was carried out to seek any prognostic significance for the expected fertility of such subjects in adulthood. All samples were also evaluated by histological and morphometric assessments, according a 1-6 grading sy-stem. In this way, the individual testicular changes were scored by quantitating tubular and germ cell hypoplasia, Sertoli cell hyperplasia, and peritubular fibrosis, where present. The results showed that in bilateral maldescended testes an unexpected expression often occurred of inhibin B beta-subunit in Sertoli cells, while inhibin B alpha-subunit there did not, denoting an early developmental arrest of the testis. It co-related with the high grade testicular damages, as a poor predictor of spermatogenesis. Unlike, unilateral retained testes mainly expressed inhibin B alpha-subunit, irrespective of tubular changes. In the latter instance, different pathogenetic factors of imbalanced testicular regulation can be perspected, other than the Inhibin-Activin system.

Adolescent↗
PubMedDate not supplied

A comparative study of serum alpha-beta A immunoreactive inhibin and tumor-associated antigens CA125 and CEA in ovarian cancer.

alpha-i.r Inhibin, has been recently proposed as a useful tumor marker for mucinous ovarian carcinomas (Ca), as the widely used tumor marker for ovarian malignancies, CA125 is efficient only in nonmucinous ovarian Ca, and, together with CEA, fails to detect minimal disease and show long half-life in serum after successful surgery. Moreover, conflicting evidence has been reported as to whether inhibin in ovarian malignancies is the biologically active dimer alpha-beta A inhibin or the inactive free alpha-subunits and inhibin precursors. Serum alpha-beta A i.r inhibin. CA125 and CEA were measured preoperatively and 8 days postoperatively in 39 postmenopausal patients with ovarian cancer (13 mucinous, 15 serous and 11 different other ovarian Ca) in comparison with 20 age-matched healthy women (Controls), 18 patients with benign ovarian tumors and 10 patients with nonovarian gynecological malignancies. Serum alpha-beta A i.r inhibin values were very low in controls (0.121 U/ml; 0.060-0.250) while they were greatly elevated in both benign (67% sensitivity) and malignant ovarian tumors (100% sensitivity in mucinous Ca, 80% in serous and 90.9% in other ovarian Ca, taken as cut-off level the maximum value in Controls, 0.250 U/ml). In contrast, in non-ovarian malignancies no increased values of alpha-beta A inhibin were found (0% sensitivity). Our results on the sensitivity of CA125 and CEA are in agreement with previous studies. After successful surgery the very high concentrations of alpha-beta A i.r. inhibin were reduced very rapidly (8 days) to normal postmenopausal values in contrast to those of CA125 and CEA, that remained elevated. Serum alpha-beta A i.r inhibin seems to be very useful in monitoring after treatment the patients with any type of ovarian malignancy and specifically those with mucinous ovarian cancer.

Biomarkers, Tumor↗
PubMed1990

Developmental changes in testicular inhibin and androgen-binding protein during sexual maturation in the cynomolgus monkey, Macaca fascicularis.

Inhibin was measured by RIA in testicular extracts and plasma of cynomolgus monkeys during four stages of sexual maturation. Immunoactive inhibin levels were compared to those of another Sertoli cell secreted protein, androgen-binding protein (ABP). ABP steroid-binding (bioactive) activity was measured in testes and epididymal segments using the radiolabeled ligand [3H]dihydrotestosterone (DHT). Testicular immunoreactive inhibin concentrations were maximal in late prepubertal monkeys, 2.5-3.5 yr old, while the total testicular content of inhibin progressively increased with age into adulthood. Bioactive testicular ABP concentrations were maximal during the pubertal period of the cynomolgus monkey (3.5-4.0 yr old), while the total ABP content of the testes also increased with sexual maturation. Mean (+/- SE) plasma concentrations of inhibin and testosterone (T) in adults, 6-8 yr old (17.72 +/- 3.5 microliters inhibin equivalents/ml and 7.07 +/- 2.45 ng/ml T, respectively), were significantly higher (P less than 0.05 and P less than 0.001, respectively) than those in early prepubertal, juvenile monkeys, aged 1.5-2.5 yr (5.85 +/- 2.1 microliters inhibin equivalents/ml and 0.27 +/- 0.02 ng/ml T). The increased plasma levels of inhibin and T in adults were associated, respectively, with the increased inhibin and androgen contents of the testes in these same animals. The developmental changes in testicular steady state mRNA concentrations for the inhibin alpha-, beta A-, and beta B-subunits as well as ABP were examined during sexual maturation by Northern blot analysis using heterologous human cDNA probes. Densitometric analysis of the autoradiograms revealed that the inhibin alpha-subunit mRNA concentrations were higher than those of inhibin-beta A and -beta B and ABP mRNA during all stages of pubertal development. Although the relative concentrations of each inhibin subunit mRNA were decreased in the adult animals relative to those in the juvenile monkeys, the total amount of steady state mRNA for the subunits was greater than that in the immature animals. A similar situation existed for the ABP mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1994

Sex difference in the action of activin-A on cell proliferation of differentiating rat gonad.

The effect of recombinant bovine activin-A on DNA synthesis in fetal rat gonads and mesonephroi was studied in vitro by using [3H]thymidine autoradiography to evaluate the role of activin in the regulation of gonadal development. mRNA levels of inhibin-beta A and -beta B, activin receptor II and IIB (ActRII and ActRIIB), and follistatin were studied by Northern hybridization in the fetal rat gonads and mesonephroi. Activin stimulated thymidine incorporation in ovaries and female mesonephroi on days 14 and 15 postcoitum (pc) in a dose-dependent manner, as assessed by autoradiography. In contrast, activin inhibited thymidine incorporation in testes and male mesonephroi on day 14 pc in a dose-dependent way. On day 18 pc, the stimulatory effect of activin in ovary was nearly lost, whereas that in mesonephros was still pronounced. Activin had no effect on thymidine incorporation in testes and male mesonephroi on day 15 or 18 pc. Inhibin-beta A mRNA was seen in testes and mesonephroi in the male and in mesonephroi in the female of 15 and 18 day pc embryos. Inhibin-beta A mRNA expression was also seen in the testes and epididymes of newborn male rats and in the ovaries of 11-day-old postnatal rats. Inhibin-beta B mRNA was present in both testes and ovaries from 15 day pc onward. ActRIIB mRNA was most abundant in the testes, ovaries, and mesonephroi of 15 day pc embryos. The expression of ActRIIB message diminished during aging. ActRII mRNA was ubiquitously expressed during development. Follistatin mRNA was seen in the ovaries from 15 day pc onward and in the oviducts at 11 days postnatally. The present novel findings of activin subunit and receptor mRNA expression and activin action on gonadal and mesonephric cell proliferation suggest an important, sexually dimorphic role for this substance in fetal gonadal differentiation.

Activin Receptors↗