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PubMed2006

Expression of bone morphogenetic proteins (BMPs), their receptors, and activins in normal and scarred conjunctiva: role of BMP-6 and activin-A in conjunctival scarring?

Bone morphogenetic proteins (BMPs) and activins are multifunctional growth factors, which also affect wound healing and tissue fibrosis. To determine their putative role in conjunctival wound healing and scarring, we investigated the expression of various BMPs, BMP receptors, and activins in normal and scarred human conjunctival tissue and in cultured human Tenon's capsule fibroblasts on the mRNA and protein level. Messenger RNA expression of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, the BMP receptors type I (BMPR-IA, BMPR-IB) and II (BMPR-II), and of activin A and B was investigated by semi-quantitative RT-PCR in normal conjunctival specimens and in scarred filtering blebs as well as in cultured Tenon's capsule fibroblasts obtained from patients with primary open-angle glaucoma (POAG), pseudoexfoliation (PEX) glaucoma and cataract. Immunohistochemistry was used to study the protein expression of BMP-2, BMP-4, BMP-6, BMP-7, and activin A in normal and scarred conjunctival tissue as well as in cultured Tenon's capsule fibroblasts. BMP-2, BMP-3, BMP-4, BMP-6, BMP-7, all BMP receptors, and activin A were expressed on the mRNA and protein level in conjunctival biopsies without showing any differences between groups of patients. The mRNA and protein expression of both BMP-6 and activin A was found to be significantly increased in scar tissue compared with normal conjunctiva and could be immunolocalized to epithelial cells, vascular endothelia, stromal fibroblasts, and macrophage-like cells. However, no significant increase in receptor gene expression was observed in scar tissue. With the exception of BMP-7, all growth factors and receptors were also expressed in cultured Tenon's fibroblasts without showing any differences between cultures derived from normal and scarred conjunctival specimens. These findings suggest various BMPs and activin A as components of the conjunctival cytokine meshwork regulating tissue homeostasis and wound healing and provide evidence that alterations in the expression of BMP-6 and activin A, in particular, are associated with conjunctival scarring. Modulation of BMP/activin activities may, therefore, be explored as new approaches for managing postoperative conjunctival scarring responses in glaucoma patients.

Activins↗
PubMed1996

Distinct localization of two serine-threonine kinase receptors for activin and TGF-beta in the rat brain and down-regulation of type I activin receptor during peripheral nerve regeneration.

The localizations of serine-threonine kinase receptor mRNA for the novel type I TGF-beta and/or activin receptor named B1 (rat), ALK-4 (mouse) or ActR-IB (human) were demonstrated by in situ hybridization. As the putative ligand for this receptor in the brain has not yet been clearly determined, we compared its localization to type II activin receptor (ActR-II) which is the counterpart of the type I activin receptor. B1 mRNA was widely observed in neuronal cells throughout the brain, and especially strong positive signals were found in the cerebral cortex, olfactory tubercle, and hippocampus. The localization of B1 mRNA coincided well with that of ActR-II. This strongly suggests that B1 (ALK-4/ActR-IB) could be the type I activin receptor, as type I and type II activin receptor were supposed to form a receptor complex. In addition, we examined the localization of type II TGF-beta receptor (TbetaRII) mRNA which is an essential counterpart of the type I TGF-beta receptors for TGF-beta signaling. TbetaRII mRNA was expressed mainly in non-neuronal cells such as choroid plexus. In addition, TbetaRII mRNA expression was also found in a minor population of neuronal cells. TbetaRII mRNA-positive neurons were observed in the reticular thalamus, laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and the ventral tegmental nucleus. The localization of TbetaRII was markedly different from that of activin receptors in the rat brain. Since TGF-betas and activins are known as growth factors and/or survival factors, we examined changes in levels of B1 and TbetaRII mRNA expression during peripheral nerve regeneration. Expression of B1 mRNA in the axotomized hypoglossal motoneurons was substantially decreased from day 3 after axotomy and this decrease was significant until postoperative day 28, whereas no TbetaRII signal was observed in hypoglossal nucleus prior or after axotomy. This transient down-regulation of B1 mRNA expression suggests that activin signaling is somehow suppressed during peripheral nerve regeneration.

Activin Receptors↗
PubMed2003

Changes in activin and activin receptor subunit expression in rat liver during the development of CCl4-induced cirrhosis.

Amounts of betaA-activin, betaC-activin, activin receptor subunits ActRIIA and ActRIIB mRNA, and betaA- and betaC-activin subunit protein immunoreactivity were investigated in male Lewis rats, either untreated or after 5 or 10 weeks of CCl(4) treatment to induce cirrhosis. Apoptosis was assessed histologically and with an in situ cell death detection kit (TUNEL). Reverse transcription and polymerase chain reaction were used to evaluate mRNA levels. Activin betaA- and betaC-subunit immunoreactivity was studied by immunohistochemistry using specific monoclonal antibodies. Hepatocellular apoptosis (P<0.001), increased betaA- and betaC-activin mRNAs (three- to fourfold; P<0.01) and increased betaA- and betaC-activin tissue immunoreactivity were evident, whereas ActRIIA mRNA concentrations fell (30%; P<0.01) after 5 weeks of CCl(4) treatment. The mRNA concentrations at 10 weeks were not significantly different from controls, despite extensive hepatic nodule formation. We conclude that the increased activin subunit expression is associated with apoptosis, rather than hepatic fibrosis and nodule formation.

Activin Receptors, Type II↗
PubMed1998

Smad7 is an activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells.

Members of the transforming growth factor-beta (TGF-beta) family, which includes the activins, relay signals from serine/threonine kinase receptors in membrane to nucleus via intracellular Sma- and Mad-related (Smad) proteins. Inhibitory Smad proteins were found to prevent the interaction between the serine/threonine kinase receptors and pathway-restricted Smad proteins. Smad7 was identified as a TGF-beta-inducible antagonist of TGF-beta signaling, and it may participate in a negative feedback loop to control TGF-beta signaling. Here we demonstrate that the mRNA expression of Smad7 is induced by activin A in mouse B cell hybridoma HS-72 cells, which undergo growth arrest and apoptosis upon exposure to activin A. The ectopic expression of mouse Smad7 in HS-72 cells suppressed the activin A-induced cell cycle arrest in the G1 phase by abolishing the activin A-induced expression of p21(CIP1/WAF1) and hypophosphorylation of retinoblastoma protein. Furthermore, Smad7 expression suppressed activin A-induced apoptosis in HS-72 cells. Thus, our data indicate that Smad7 is an activin A-inducible antagonist of activin A-induced growth arrest and apoptosis of B lineage cells.

Activins↗
PubMed1998

A longitudinal study of maternal serum inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC and follistatin during pregnancy.

Maternal serum concentrations of inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC-related inhibin forms, total follistatin, steroids and gonadotrophins were measured longitudinally in six normal singleton pregnancies. Maternal venous blood was collected randomly during a spontaneous follicular phase prior to donor insemination, at 5, 7, 9, 11, 16, 20, 24, 28, 32 and 36 weeks after the first missed menses and in the early puerperium. Steroid and gonadotrophin profiles conformed to previous reports. While at week 5 of gestation inhibin-A, activin-A and follistatin concentrations were similar to those at the follicular phase, all three increased progressively (P < 0.001) to maximal concentrations in week 36: approximately 48-fold (3740 +/- 1349 ng inhibin-A/ml), approximately 22-fold (6109 +/- 1443 ng activin-A/ml) and approximately 10-fold (3563 +/- 418 ng follistatin/ml) higher. Pro-alphaC concentrations reached a maximum in weeks 5 (approximately 5-fold, P < 0.001) and 36 (1027 +/- 174 pg/ml, P < 0.01). Inhibin-B (71 +/- 23 pg/ml prior to pregnancy) was undetectable (<12 pg/ml) between week 5-16 of gestation but increased slightly in the third trimester (26 +/- 7 pg/ml in week 36). Activin-AB was undetectable throughout pregnancy. Post-partum concentrations of inhibin-A (41 +/- 12 ng/ml), inhibin-B (<12 pg/ml), activin-A (950 +/- 149 pg/ml), pro-alphaC (128 +/- 22 pg/ml) and follistatin (990 +/- 79 ng/ml) were substantially lower than at week 36 of gestation. The activin-A:follistatin ratio increased from 0.5 in week 5 to 1.8 in week 36, suggesting that more free activin-A is available in the maternal circulation during late pregnancy.

Activins↗
PubMed1998

A two-site chemiluminescent assay for activin-free follistatin reveals that most follistatin circulating in men and normal cycling women is in an activin-bound state.

Follistatin (FS) is a monomeric protein that binds and regulates the bioavailability of activin. Previously, we found circulating levels of total FS to be similar in men and cycling women. Because relative amounts of activin-bound and free FS are important considerations in determining activin bioavailability, we asked here whether the relative proportions of these two changed during different physiologic states. For this, we developed a two-site, solid-phase, immunochemiluminescent assay for free FS. The assay recognizes the 288 or 315 amino acid variants of human FS and has a detectable limit of 1 ng/mL. Inhibin, transforming growth factor-beta, or alpha-2-macroglobulin do not cross-react or interfere in this assay. Preincubation of FS with activin results in dose-dependent loss of immunoreactivity, confirming specificity of the assay for free FS. Human follicular fluid, pituitary extract, and serum with added FS dilute parallel with the recombinant human FS-288 standard. Recovery of recombinant human FS-288 from serum is quantitative. Using this assay, we found circulating concentrations of free FS to be at or below the detection limit of the assay throughout the menstrual cycle. Comparison of circulating total and free FS levels in postmenopausal or cycling women and normal men suggested that at least 90% is activin-bound. In contrast, measurable quantities of free FS were found in follicular fluid and pituitary extracts. The results of this study, showing that most circulating FS is normally activin-bound, argue against an endocrine role for FS and suggest that a major role of circulating FS is to bind and neutralize the bioactivity of circulating activin. The roles of FS as a local autocrine or paracrine regulator of activin in target tissues, where FS exists in free form, or as an endocrine regulator in human pathophysiology, warrants further investigation.

Activins↗
PubMed2002

Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers.

Activins are cytokines of the transforming growth factor beta family, which plays a central role in the determination of cell fate and the regulation of tissue balance. Family members are composed of two subunits and this dimerization is critical for liganding their cognate receptors and execution of proper functions. In the current study we focused on the localization of activin betaA, betaB, betaC and betaE subunits in the adult rat and analyzed the composition of putative activin beta dimers. By dissecting tissue distribution of various activins, we found that the liver, in particular the hepatocytes, is the major source for activin betaC and betaE transcripts, since other tissues almost failed to express these isoforms. In sharp contrast, the emergence of activin betaA and betaB appeared ubiquitous. Using a highly selective proteome approach, we were able to identify homo- as well as heterodimers of individual activin subunits, indicating a high redundancy of ligand composition. Certainly, this broad potential to homo- and heterodimerize has to be considered in future studies on activin function.

Activins↗
PubMedDate not supplied

Localization of Activin and Activin Receptors in Rat Spinal Motoneurons.

The purpose of this experiment was to determine whether rat spinal motoneurons (a) produce activin protein and (b) transcribe mRNAs coding for the betaA-subunit of activin and activin receptors II and IIB. The production of activin was determined by immunocytochemistry. The expression and localization of the mRNAs were elucidated by the reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization techniques. We have observed that activin A protein was produced and mRNAs encoding activin betaA-subunit and activin receptors II and IIB were expressed by motoneurons of the rat spinal cord. Furthermore, the identity of RT-PCR products was confirmed by DNA sequencing. It is concluded that activin may have a functional role in the maintenance of rat spinal motoneurons. Copyright 1996 S. Karger AG, Basel

Journal Article↗
PubMed2004

Expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation.

The formation of the essential functional unit of the ovary, the primordial follicle, occurs during fetal life in humans. Factors regulating oogonial proliferation and interaction with somatic cells before primordial follicle formation are largely unknown. We have investigated the expression, localisation and functional effects of activin and its receptors in the human fetal ovary at 14-21 weeks gestation. Expression of mRNA for the activin betaA and betaB subunits and the activin receptors ActRIIA and ActRIIB was demonstrated by RT-PCR. Expression of betaA mRNA increased 2-fold across the gestational range examined. Activin subunits and receptors were localised by immunohistochemistry. The betaA subunit was expressed by oogonia, and the betaB subunit and activin receptors were expressed by both oogonia and somatic cells. BetaA expression was increased in larger oogonia at later gestations, but was low in oocytes within newly formed primordial follicles. Treatment of ovary fragments with activin A in vitro increased both the number of oogonia present and oogonial proliferation, as detected by bromodeoxyuridine (BrdU) incorporation. These data indicate that activin may be involved in the autocrine and paracrine regulation of germ cell proliferation in the human ovary during the crucial period of development leading up to primordial follicle formation.

Activin Receptors, Type II↗
PubMed1995

Different phenotypes for mice deficient in either activins or activin receptor type II.

Activins are believed to initiate a signal transduction cascade by binding to serine/threonine kinase receptors types I and II. Activins bind to several different receptors in vitro, but the significance of this interaction in vivo has not been confirmed. To test the function of the type II activin receptor (ActRcII) in mammalian development and reproduction, we generated a null mutation in the ActRcII gene in mice using embryonic stem cell technology. We expected ActRcII-deficient mice to phenocopy activin-deficient mice. A few ActRcII-deficient mice had skeletal and facial abnormalities reminiscent of the Pierre-Robin syndrome in humans, but most lacked these defects and developed into adults; their follicle-stimulating hormone was suppressed, and their reproductive performance was defective. These findings confirm a role of ActRcII in activin signalling in pituitary gonadotrophs. The striking lack of overlap between phenotypes of ActRcII-deficient and activin-deficient mice suggests that the ligands that signal through ActRcII during embryonic development are not activins.

Activin Receptors↗
PubMed2001

Activin A and activin receptors in thyroid cancer.

Proliferation is controlled by a network of mitogenic and growth inhibitory factors. Transforming growth factor-beta1 (TGF-beta1) and activin A are the most important growth inhibitors of benign follicular epithelial cells of the human thyroid. The effects of these substances on malignant primary thyrocytes are not known. We have examined the growth regulatory effects of activin A and TGF-beta1 in primary cultures derived from four papillary cancers, two follicular thyroid cancers, and three benign thyroid tissues. Malignant cells demonstrated resistance to activin and TGF-beta1 or reversal to a weak but significant mitogenic effect (p < 0.001). We also evaluated the activin receptor transcription pattern. Isoforms alk4-1, 4-2, and 4-3 were found in benign (n = 12) and malignant (n = 22) tissues. Two subtypes of type I and type II activin receptors were demonstrated. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated a significant threefold downregulation of alk4-1 receptors in papillary (n = 25) and follicular (n = 18) thyroid cancers as compared to normal thyroids (n = 12) (p < 0.001). To our knowledge these are the first data to demonstrate reversal of activin and TGF-beta1 effects in thyroid malignancy and to demonstrate changes of the type Ib activin receptor expression in thyroid malignancy.

Activin Receptors↗
PubMed2000

Gene expression of activin, activin receptors, and follistatin in intestinal epithelial cells.

Gene expression of activin, activin receptors, and follistatin was investigated in vivo and in vitro using semiquantitative RT-PCR in intestinal epithelial cells. Rat jejunum and the intestinal epithelial cell line IEC-6 expressed mRNA encoding the betaA-subunit of activin, alpha-subunit of inhibin, activin receptors IB and IIA, and follistatin. An epithelial cell isolation study focused along the crypt-villus axis in rat jejunum showed that betaA mRNA levels were eight- to tenfold higher in villus cells than in crypt cells. Immunohistochemistry revealed the expression of activin A in upper villus cells. The human intestinal cell line Caco-2 was used as a differentiation model of enterocytes. Four- to fivefold induction of betaA mRNA was observed in postconfluent Caco-2 cells grown on filter but not in those cells grown on plastic. In contrast, follistatin mRNA was seen to be reduced after reaching confluence. Exogenous activin A dose-dependently suppressed the proliferation and stimulated the expression of apolipoprotein A-IV gene, a differentiation marker, in IEC-6 cells. These results suggest that the activin system is involved in the regulation of such cellular functions as proliferation and differentiation in intestinal epithelial cells.

Activin Receptors↗
PubMed2003

Activin signaling through type IB activin receptor stimulates aromatase activity in the ovarian granulosa cell-like human granulosa (KGN) cells.

In addition to a stimulatory effect on FSH production by the pituitary gland, activin is thought to have a paracrine or autocrine role in follicular development in the ovary, where it is produced. Recently, we established a human ovarian granulosa tumor cell line, KGN, which possesses in vivo characteristics of granulosa cells, namely the expression of functional FSH receptors and cytochrome P-450 aromatase. Here, we have demonstrated the activin signaling pathway and its role in KGN cells. A series of transient transfection experiments revealed that activin type IB receptor (ActRIB) is an essential component of the activin signaling pathway in KGN cells. Smad2 was found to act downstream of ActRIB as an intracellular signal transmitter. Smad7, but not Smad6, was an inhibitory Smad in the pathway. Finally, we show that FSH receptor expression and cytochrome P-450 (P-450) aromatase activity was up-regulated by activin stimulation through ActRIB in KGN cells. These results show that we have clarified the signaling mechanisms and the roles of activin in the human granulosa cell line, KGN. Activin signaling mediated by ActRIB-Smad2 system in the ovary may thus be essential for the regulation of follicular differentiation.

Activin Receptors, Type I↗
PubMed1997

Activins and activin receptors in cell growth.

Activin and inhibin, members of transforming growth factor-beta (TGFbeta) superfamily, have diverse and widespread effects within living organisms at many stages during growth and development. From the initial isolation of these growth factors based on their effects of FSH secretion, the study of these factors, as well as of the activin-binding protein follistatin, has progressed from the localization of the expression of the inhibin alpha subunit, activin betaA and betaB subunits, and activin receptors in the tissues of various organisms to the examination of activin and inhibin as autocrine and paracrine agents in cell proliferation and differentiation. The inhibitory effects on cell growth and differentiation that have been observed upon treatment of cells with activin suggest that further understanding of the bioactivity of this molecule and its characterization on a molecular level may aid in a more complete understanding of cell growth and differentiation. This minireview discusses the roles of activin, inhibin, and follistatin in the arenas of cell proliferation, differentiation, and embryogenesis, as well as the roles of these molecules in cancerous cells.

Activin Receptors↗
PubMed1998

Differential expression of activin subunits, activin receptors and follistatin genes in bovine oocytes and preimplantation embryos.

The presence of inhibin subunits (alpha, betaA and betaB), activin binding protein follistatin and activin receptors (ActR-I, ActR-IB, ActR-II and ActR-IIB) mRNA transcripts in bovine oocytes and preimplantation embryos was examined by reverse transcription-polymerase chain reaction. Immature and matured oocytes, zygotes, 2-cell, 3-4-cell, 5-8-cell, 9-16-cell embryos, morulae, blastocysts and hatched blastocysts were produced by in vitro maturation, fertilization and culture for this study. Activin betaA subunit and follistatin transcripts were detected in all of the stages tested. However, alpha subunit transcripts were detected only in oocytes (immature and matured), blastocysts and hatched blastocysts, and no betaB subunit transcripts were found in any of the stages. Whereas ActR-I transcripts were detectable in all stages, ActR-IB transcripts were not detectable in oocytes or embryos except in matured oocytes. Activin type II receptors (ActR-II and ActR-IIB) transcripts were detectable in oocytes and embryos except for ActR-IIB, which was not found in the 5-8-cell stage embryos. The results suggest that bovine embryos may produce activin A (homodimer of the betaA subunits) at least from zygotes to morulae. Furthermore, bovine oocytes and embryos express the activin receptors mainly by the combination of ActR-I and either ActR-II or ActR-IIB.

Activin Receptors↗
PubMed1993

Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat. I. Serum profile of rh-inhibin A and rh-activin A in the immature female rat.

The serum pharmacokinetics of recombinant human inhibin A (rh-inhibin A) and rh-activin A were examined in immature female Sprague Dawley-derived rats after iv and sc injection of the drugs. After iv administration of rh-inhibin A (120 micrograms/kg), the serum concentrations were described by a biexponential equation. The weight-normalized clearance was 21.3 ml/min.kg, and the initial (t1/2 alpha) and terminal (t1/2 beta) half-lives were 2.9 min and 37.9 min, respectively. Subcutaneous administration of 120 micrograms/kg rh-inhibin A resulted in a peak serum concentration of 10.6 ng/ml at 30.8 min after injection. Approximately 24% of the sc administered material was absorbed. Serum concentrations of rh-activin A also declined biexponentially after iv injection of the drug (120 micrograms/kg). The clearance of rh-activin A was 5.1 ml/min.kg, the t1/2 alpha was 6.1 min, and the t1/2 beta was 46.3 min. The peak serum concentration of rh-activin A (104.7 ng/ml) was achieved 24.7 min after sc delivery of the drug. The bioavailability of the sc dose was 38%. Iodinated rh-inhibin A and rh-activin A were used to examine the serum forms and metabolites of the drugs. [125I]rh-inhibin A and [125I]rh-activin A associated with two serum-binding proteins. Within 2 min of iv injection, the labeled hormones bound follistatin and alpha-2-macroglobulin. Even though rh-inhibin A and rh-activin A are structurally similar and appear to bind to the same serum proteins, their disposition in the immature rat differ.

Activins↗
PubMed1993

Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat. II. Tissue distribution of [125I]rh-inhibin A and [125I]rh-activin A in immature female and male rats.

The tissue distribution of recombinant human inhibin A (rh-inhibin A) and rh-activin A was determined in immature female Sprague Dawley-derived rats after iv administration of radiolabeled proteins. [125I]rh-Inhibin A and [125I]rh-activin A diverge in their distribution to tissues of the immature female rat as examined histologically (whole body autoradiography and thin section analysis) and by computing the percent dose and tissue to blood ratios for individual tissues. [125I]rh-inhibin A accumulated in the spleen, adrenal, bone marrow, and ovary after iv injection. Iodinated rh-inhibin A was also found in the anterior and posterior pituitary. [125I]rh-activin A was found in the ovary and pituitary after iv injection. Little specific binding was found in the spleen or adrenal. The bone marrow accumulated some [125I]rh-activin A which was competed by rh-activin A. The primary route of excretion for radioactivity was the kidney, with the label appearing in the bladder by 10 min after iv injection. Not only do rh-inhibin A and rh-activin A have different pharmacokinetics, but fewer tissues accumulate radioactive rh-activin A than rh-inhibin A.

Activins↗
PubMed1993

Increased follistatin (activin-binding protein) gene expression in rat anterior pituitary tissue after ovariectomy may be mediated by pituitary activin.

For lack of evidence to the contrary, it is now believed that the FSH-suppressing actions of follistatin are due to its ability to bind endogenous pituitary activin. Recent data have demonstrated a role for pituitary activin-B in mediating FSH hypersecretion after ovariectomy (OVX) and during the secondary FSH surge on estrus. Therefore, given that follistatin is produced within anterior pituitary tissue, and considering the potentially important function of follistatin to modulate activin bioactivity, we sought to gain insights into the regulation of follistatin gene expression in the anterior pituitary gland of adult female rats. At the termination of all in vivo investigations, rats were killed, trunk blood was collected for determination of serum LH and FSH levels by RIA, and pituitary tissue was collected, pooled (two or three glands per pool), and processed for determination of follistatin messenger RNA (mRNA) levels by a solution-hybridization RNase protection assay. In the first experiment, pituitary follistatin mRNA levels were significantly (P < 0.01) increased 3 weeks after OVX. Treatment of long-term ovariectomized rats with a Nal-Glu LHRH antagonist restored serum LH levels to precastration levels and suppressed serum FSH concentrations by 70%, but follistatin message levels were not altered. In contrast, treatment of castrated rats with recombinant human follistatin-288 selectively suppressed serum FSH levels (50%) and completely abolished OVX-induced increases in follistatin mRNA levels. Subsequent experiments revealed that OVX-induced increases in follistatin gene expression could be observed in pituitary tissue grafted underneath the kidney capsule of hypophysectomized rats. Furthermore, follistatin mRNA levels were significantly (P < 0.05) higher in pituitary glands taken from estrous rats during the secondary FSH surge (0200 h) than in glands obtained from rats on proestrous morning when serum FSH levels were basal. Because increased steady state follistatin mRNA levels in the latter two instances were associated with selective FSH hypersecretion, and such hypersecretion was previously shown to be dependent to a significant degree on pituitary activin, we next tested the hypothesis that increased pituitary follistatin gene expression is mediated by activin. Using cultures of dispersed pituitary cells, addition of recombinant human activin-A for 72 h increased follistatin mRNA levels 3-fold while enhancing only FSH secretion. Collectively, the present results demonstrate a coupling of follistatin gene expression in the anterior pituitary gland with changes in pituitary FSH secretion under conditions where LH secretion is unaltered. Viewed in the context of previous work, the data also suggest that changes in follistatin mRNA levels may be linked to activin signaling.

Activins↗