Rat follistatin: Ontogeny of steady-state mRNA levels in different tissues predicts organ-specific functions

doi:10.1016/S0006-291X(05)81280-X

Biochemical and Biophysical Research Communications

Volume 180, Issue 1, 15 October 1991, Pages 223-230

https://doi.org/10.1016/S0006-291X(05)81280-X Get rights and content

Follistatin (FS), a monomeric glycoprotein which specifically binds activin, is expressed in many tissues. This study investigated 1) the ontogeny of the steady-state FS mRNA levels in different extragonadal tissues and 2) whether the ratio of the differential splicing products, FS 344 or its carboxy-truncated form FS 317, is changed during postnatal development. Whereas the levels of FS mRNA 344 in the kidney showed a profound increase from the day of birth to adulthood, the levels in the muscle peaked during the infantile period and then declined. Brain cortex, heart and thymus also showed tissue specific expression in the steady-state mRNA level of FS during postnatal development. None of the tissues showed a measurable change in the ratio of the mRNA for FS 344 and FS 317. The FS mRNA 344 levels in male and female kidney were not different. It is concluded that the ontogeny of steady state FS mRNA varies in a tissue specific manner during postnatal development of the rat and may be involved in modulating the outcome of activin.

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Follistatin dysregulation impaired trophoblast biological functions by GDF11-Smad2/3 axis in preeclampsia placentas
2022, Placenta
Citation Excerpt :
Removal of the signal peptide yielded mature polypeptides of 315 (FST315) and 288 (FST288) amino acids. The longer FST315 variant was predominant whereas FST288 accounted for less than 5% of the encoded mRNA [10]. FST315 may also be proteolytically cleaved in vivo at the C-terminal end to yield an ∼300 amino acid form (FST300) [11].
Preeclampsia (PE) is one of the main causes of maternal, fetal, and neonatal mortality. So far, the underlying mechanism of this pregnancy-specific syndrome remains unelucidated. The expression of Follistatin (FST) decreased in maternal serum (especially early onset severe PE) and placental trophoblasts of PE patients. However, whether FST-deficiency in preeclamptic placentas alters trophoblast function remains to be determined.
Trophoblast cell lines were cultured in vitro and LV3 short hairpin RNA (shRNA) was used to silence FST. Growth and differentiation factor 11 (GDF11) expression level in placentas and serum were detected by immunohistochemistry and enzyme-linked immune-sorbent assay, respectively. To verify the effect of reduced FST expression on trophoblasts, microRNA-24-3p, which was predicted to target the 3′-untranslated region (3′-UTR) of FST, was screened out, and miR-24-3p mimic, inhibitor was used to regulate FST expression in trophoblasts.
Downregulation of FST significantly enhanced the apoptosis and impaired migration and invasion of trophoblast. Reduced FST caused the upregulation of GDF11 in trophoblasts. Interestingly, GDF11 reduced in preeclamptic placental microvascular endothelial cells. Dysregulation of FST-GDF11-Smad2/3 signaling pathway, leading to increased apoptosis of trophoblast. Expression levels of miR-24-3p, was significantly elevated in preeclamptic placentas. Trophoblast cells transfected with miR-24-3p mimics displayed impaired migration and invasion and increased apoptosis. Treated by miR-24-3p inhibitor, trophoblast cells exhibited rescued function.
FST-deficiency impaired trophoblast function by upregulating GDF11 levels in trophoblasts. The regulation of FST-GDF11-Smad2/3 axis by microRNAs mimic or inhibitor may be critical to trophoblast function regulation and helps to deepen our understanding of the molecular mechanism of PE.
New insights into the mechanisms of activin action and inhibition
2012, Molecular and Cellular Endocrinology
Citation Excerpt :
None of these proteins however have reported activin binding activities, suggesting they are not functional analogues of the FST proteins. FST is expressed in most tissues where activin is observed (Michel et al., 1991; Tuuri et al., 1994; Welt et al., 2002), but is abundant in the ovary (Arai et al., 2002) and pituitary (Besecke et al., 1997; Bilezikjian et al., 2004). In contrast, FSTL-3 is maximally expressed in the placenta (Ciarmela et al., 2003), testis (Xia et al., 2004), skin (Wankell et al., 2001), adrenal glands, heart (Xia et al., 2004), endometrium (Florio et al., 2004), skeletal muscle (Allen et al., 2008) and cardiovascular tissue (Takehara-Kasamatsu et al., 2007), suggesting tissue specific roles of the two classes of FST proteins.
Like other members of the transforming growth factor-β (TGF-β) superfamily, activins are synthesised as precursor molecules comprising an N-terminal prodomain and C-terminal mature region. During synthesis, the prodomain interacts non-covalently with mature activin, maintaining the molecule in a conformation competent for dimerisation. Dimeric precursors are cleaved by proprotein convertases and activin is secreted from the cell non-covalently associated with its propeptide. Extracellularly, the propeptide interacts with heparan sulfate proteoglycans to regulate activin localization within tissues. The mature activin dimer exhibits the classic ‘open-hand’ structure of TGF-β ligands with ‘finger-like’ domains projecting outward from the cysteine knot core of the molecule. These finger domains form the binding epitopes for type I and II serine/threonine kinase receptors. Activins ability to access its signalling receptors is regulated by the extracellular binding proteins, follistatin, follistatin-like-3, and by inhibins, which, in the presence of betaglycan, sequester type II receptors.
A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys
2010, Bone
Citation Excerpt :
The actions of ACE-011 may parallel the role of follistatin, an endogenous soluble protein which binds multiple TGF-β ligands, including activin, and prevents them from interacting with their receptors [25]. Follistatin is expressed locally in most of tissues that also express activin [26–30], including muscle, brain, kidney, salivary gland, liver, adrenal gland, ovary, testis and bone, but is not found at high levels in circulation, indicating that it may act in a paracrine manner to block ligand signaling. In bone cells, follistatin transcript is detected in osteoblasts [30], osteocytes [30] and MC3T3-E1 cells [31].
Activin A belongs to the TGF-β superfamily and plays an important role in bone metabolism. It was reported that a soluble form of extracellular domain of the activin receptor type IIA (ActRIIA) fused to the Fc domain of murine IgG, an activin antagonist, has an anabolic effect on bone in intact and ovariectomized mice. The present study was designed to examine the skeletal effect of human ActRIIA-IgG1-Fc (ACE-011) in non-human primates. Young adult female Cynomolgus monkeys were given a biweekly subcutaneous injection of either 10 mg/kg ACE-011 or vehicle (VEH) for 3 months. Treatment effects were evaluated by histomorphometric analysis of the distal femur, femoral midshaft, femoral neck and 12th thoracic vertebrae, by μCT analysis of femoral neck and by biomarkers of bone turnover. Compared to VEH, at the distal femur ACE-011-treated monkeys had significantly increased cancellous bone volume (+ 93%), bone formation rate per bone surface (+ 166%) and osteoblast surface (+ 196%) indicating an anabolic action. Monkeys treated with ACE-011 also had decreased osteoclast surface and number. No differences were observed in parameters of cortical bone at the midshaft of the femur. Similar to distal femur, ACE-011-treated monkeys had significantly greater cancellous bone volume, bone formation rate and osteoblast surface at the femoral neck relative to VEH. A significant increase in bone formation rate and osteoblast surface with a decrease in osteoclast surface was observed in thoracic vertebrae. μCT analysis of femoral neck indicated more plate-like structure in ACE-011-treated monkeys. Monkeys treated with ACE-011 had no effect on serum bone-specific alkaline phosphatase and CTX at the end of the study. These observations demonstrate that ACE-011 is a dual anabolic-antiresorptive compound, improving cancellous bone volume by promoting bone formation and inhibiting bone resorption in non-human primates. Thus, soluble ActRIIA fusion protein may be useful in the prevention and/or treatment of osteoporosis and other diseases involving accelerated bone loss.
The activin axis in liver biology and disease
2006, Mutation Research - Reviews in Mutation Research
Activins are a closely related subgroup within the TGFβ superfamily of growth and differentiation factors. They consist of two disulfide-linked β subunits. Four mammalian activin β subunits termed β_A, β_B, β_C, and β_E, respectively, have been identified. Activin A, the homodimer of two β_A subunits, has important regulatory functions in reproductive biology, embryonic development, inflammation, and tissue repair. Several intra- and extracellular antagonists, including the activin-binding proteins follistatin and follistatin-related protein, serve to fine-tune activin A activity. In the liver there is compelling evidence that activin A is involved in the regulation of cell number by inhibition of hepatocyte replication and induction of apoptosis. In addition, activin A stimulates extracellular matrix production in hepatic stellate cells and tubulogenesis of sinusoidal endothelial cells, and thus contributes to restoration of tissue architecture during liver regeneration. Accumulating evidence from animal models and from patient data suggests that deregulation of activin A signaling contributes to pathologic conditions such as hepatic inflammation and fibrosis, acute liver failure, and development of liver cancer. Increased production of activin A was suggested to be a contributing factor to impaired hepatocyte regeneration in acute liver failure and to overproduction of extracellular matrix in liver fibrosis. Recent evidence suggests that escape of (pre)neoplastic hepatocytes from growth control by activin A through overexpression of follistatin and reduced activin production contributes to hepatocarcinogenesis. The role of the activin subunits β_C and β_E, which are both highly expressed in hepatocytes, is still quite incompletely understood. Down-regulation in liver tumors and a growth inhibitory function similar to that of β_A has been shown for β_E. Contradictory results with regard to cell proliferation have been reported for β_C. The profound involvement of the activin axis in liver biology and in the pathogenesis of severe hepatic diseases suggests activin as potential target for therapeutic interventions.
Follistatin: A multifunctional regulatory protein
1998, Frontiers in Neuroendocrinology
Follistatin was first described in 1987 as a follicle-stimulating hormone inhibiting substance present in ovarian follicular fluid. We now know that this effect of follistatin is only one of its many properties in a number of reproductive and nonreproductive systems. A majority of these functions are facilitated through the affinity of follistatin for activin, where activin's effects are neutralized through its binding to follistatin. As such, the interplay between follistatin and activin represents a powerful regulatory mechanism that impinges on a variety of cellular processes within the body. In this review we focus on the biochemical characteristics of follistatin and its interaction with activin and discuss the emerging role of these proteins as potent tissue regulators in the gonad, pituitary gland, pregnancy membranes, vasculature, and liver. Consideration is also given to the larger family of proteins that contain follistatin-like modules, in particular with regard to their functional and structural implications.
Proceedings of The Ares-Serono Foundation Workshop on Paracrine Mechanisms in Female Reproduction, Seville, Spain, June 1997: Mechanisms of protein feedback on gonadotropin secretion
1998, Journal of Reproductive Immunology
The classical concept that the control of follicle-stimulating hormone (FSH) and luteinising hormone (LH) secretion by the pituitary gland is achieved by the stimulation of gonadotropin-releasing hormone (GnRH) and negative feedback by steroid secretion from the gonads has recently been modified by the identification of several proteins with the capacity to modulate FSH secretion. These proteins, inhibin, activin and follistatin, are produced in the ovary and testis and have the capacity to act as long loop protein feedback signals which modulate FSH secretion. Further studies indicate that inhibin probably acts as a circulating hormone to inhibit FSH secretion. More recent data suggest that activin and follistatin may act as local mediators to control FSH secretion at the pituitary by paracrine or autocrine phenomena. The production of activin, which stimulates FSH, and its binding protein follistatin, by pituitary cells raises the possibility that the local production modulates FSH secretion in addition to the long loop feedback signals emanating from the gonads through the steroid hormones estradiol and testosterone as well as circulating inhibin levels. Further studies are necessary to confirm the nature of these regulatory processes.

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Rat follistatin: Ontogeny of steady-state mRNA levels in different tissues predicts organ-specific functions

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Blood

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Endocrinol.

Endocrinology

Nature

Nature