Follistatin: A Multifunctional Regulatory Protein

doi:10.1006/frne.1998.0169

Frontiers in Neuroendocrinology

Volume 19, Issue 4, October 1998, Pages 287-322

https://doi.org/10.1006/frne.1998.0169 Get rights and content

Abstract

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.

References (236)

BM Alak et al.
Enhancement of primate oocyte maturation and fertilization in vitro by inhibin A and activin A
Fertil Steril
(1996)
H Amthor et al.
The expression and regulation offollistatinfollistatin-like
Dev Biol
(1996)
L Attisano et al.
Novel activin receptors: Distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors
Cell
(1992)
CA Campen et al.
Characterization of activin A binding sites on the human leukemia cell line K562
Biochem Biophys Res Commun
(1988)
P Colburn et al.
Alterations of heparan sulfate moieties in cultured endothelial cells exposed to endotoxin
Arch Biochem Biophys
(1996)
JP de Winter et al.
Follistatins neutralize activin bioactivity by inhibition of activin binding to its type II receptors
Mol Cell Endocrinol
(1996)
A Fainsod et al.
The dorsalizing and neural inducing genefollistatinBMP-4
Mech Dev
(1997)
JR Fallon et al.
Building synapses: Agrin and dystroglycan stick together
Trends Neurosci
(1994)
J Fang et al.
Molecular cloning of the mouse activin β_E
Biochem Biophys Res Commun
(1996)
A Fukui et al.
Isolation and characterization ofXenopus
Dev Biol
(1993)

J-P Girard et al.

Cloning from purified high endothelial venule cells of hevin, a close relative of the antiadhesive extracellular matrix protein SPARC

Immunity

(1995)

J-P Girard et al.

Modulation of endothelial cell adhesion by hevin, an acidic protein associated with high endothelial venules

J Biol Chem

(1996)

D Gospodarowicz et al.

Pituitary follicular cells secrete both vascular endothelial growth factor and follistatin

Biochem Biophys Res Commun

(1989)

O Hashimoto et al.

A novel role of follistatin, an activin-binding protein, in the inhibition of activin action in rat pituitary cells. Endocytotic degradation of activin and its acceleration by follistatin associated with cell-surface heparan sulfate

J Biol Chem

(1997)

A Hemmati-Brivanlou et al.

Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity

Cell

(1994)

A Hemmati-Brivanlou et al.

Vertebrate embryonic cells will become nerve cells unless told otherwise

Cell

(1997)

G Hötten et al.

Cloning of a new member of the TGF-β family: A putative new activin β_C

Biochem Biophys Res Commun

(1995)

S Inoue et al.

Demonstration of activin-A in arteriosclerotic lesions

Biochem Biophys Res Commun

(1994)

S Inouye et al.

Site-specific mutagenesis of human follistatin

Biochem Biophys Res Commun

(1991)

S Inouye et al.

Localization of the heparin binding site of follistatin

Mol Cell Endocrinol

(1992)

M Kanzaki et al.

Production of activin A and follistatin in cultured rat vascular smooth muscle cells

Mol Cell Endocrinol

(1995)

M Kanzaki et al.

Stimulation of follistatin production by epidermal growth factor in cultured rat hepatocytes

Biochem Biophys Res Commun

(1994)

RJ Kleiman et al.

Testing the agrin hypothesis

Cell

(1996)

PG Knight

Roles of inhibins, activins, and follistatin in the female reproductive system

Front Neuroendocrinol

(1996)

K Kogure et al.

A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized rats

Gastroenterology

(1995)

K Kogure et al.

Intravenous administration of follistatin: Delivery to the liver and effect on liver regeneration after partial hepatectomy

Hepatology

(1996)

I Kojima et al.

Modulation of growth of vascular smooth muscle cells by activin A

Exp Cell Res

(1993)

S Kondo et al.

Identification of the two types of specific receptor for activin/EDF expressed in Friend leukemia and embryonal carcinoma cells

Biochem Biophys Res Commun

(1989)

DH Kozian et al.

Rapid identification of differentially expressed endothelial cell genes by RNA display

Biochem Biophys Res Commun

(1995)

RM Albano et al.

Expression of inhibin subunits and follistatin during postimplantation mouse development: Decidual expression of activin and expression of follistatin in primitive streak, somites and hindbrain

Development

(1994)

PM Alliel et al.

Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour

Eur J Biochem

(1993)

M Asashima et al.

Follistatin inhibits the mesoderm-inducing activity of activin A and the vegetalizing factor from chicken embryo

Roux's Arch Dev Biol

(1991)

B Attardi et al.

Decay of follicle-stimulating hormone-β messenger RNA in the presence of transcriptional inhibitors and/or inhibin, activin, or follistatin

Mol Endocrinol

(1993)

AC Bauer-Dantoin et al.

Gonadotropin-releasing hormone regulation of pituitary follistatin gene expression during the primary follicle-stimulating hormone surge

Endocrinology

(1996)

LM Besecke et al.

Gonadotropin-releasing hormone regulates follicle-stimulating hormone-β gene expression through an activin/follistatin autocrine or paracrine loop

Endocrinology

(1996)

LM Besecke et al.

Pituitary follistatin regulates activin-mediated production of follicle-stimulating hormone during the rat estrous cycle

Endocrinology

(1997)

LM Bilezikjian et al.

Pituitary follistatin and inhibin subunit messenger ribonucleic acid levels are differentially regulated by local and hormonal factors

Endocrinology

(1996)

LM Bilezikjian et al.

Interleukin-1β regulates pituitary follistatin and inhibin/activin β_B

Endocrinology

(1998)

LM Bilezikjian et al.

Activin-A regulates follistatin secretion from cultured rat anterior pituitary cells

Endocrinology

(1993)

C Boitani et al.

Activin stimulates Sertoli cell proliferation in a defined period of rat testis development

Endocrinology

(1995)

R Braw-Tal

Expression of mRNA for follistatin and inhibin/activin subunits during follicular growth and atresia

J Mol Endocrinol

(1994)

R Braw-Tal et al.

Follistatin but not α or β_A

J Mol Endocrinol

(1994)

AG Byskov

The role of the rete ovarii in meiosis and follicle formation in the cat, mink and ferret

J Reprod Fertil

(1975)

RS Carroll et al.

Inhibin, activin, and follistatin: Regulation of follicle-stimulating hormone messenger ribonucleic acid levels

Mol Endocrinol

(1989)

DS Choi et al.

Activin-attenuated expression of transcripts encoding granulosa cell-derived insulin-like growth factor binding proteins 4 and 5 in the rat: A putative antiatretic effect

Biol Reprod

(1997)

S-Y Chun et al.

Hormonal regulation of apoptosis in early antral follicles: Follicle-stimulating hormone as a major survival factor

Endocrinology

(1996)

P Colburn et al.

Depleted level of heparan sulfate proteoglycan in the extracellular matrix of endothelial cell cultures exposed to endotoxin

J Cell Physiol

(1994)

AC Dalkin et al.

Pituitary activin receptor subtypes and follistatin gene expression in female rats: Differential regulation by activin and follistatin

Endocrinology

(1996)

S Damjanovski et al.

Ectopic expression of SPARC inXenopus

J Histochem Cytochem

(1997)

DM de Kretser et al.

Partial charaterization of inhibin, activin and follistatin in the term human placenta

J Clin Endocrinol Metab

(1994)

Cited by (233)

Knockdown of FSTL1 inhibits microglia activation and alleviates depressive-like symptoms through modulating TLR4/MyD88/NF-κB pathway in CUMS mice
2022, Experimental Neurology
Citation Excerpt :
Follistatin-like 1 (FSTL1), a secreted protein rich in cysteine (SPARC), is widely expressed in human and mouse tissues (Chaly et al., 2014). Since the follistain-like domain of FSTL1 was found to bind to activin, an immunologic role for FSTL1 has been investigated (Phillips and de Kretser, 1998). Previous studies have suggested that FSTL1 is important in inflammation and the regulation of immune cell function in the pathogenesis of rheumatoid arthritis and other immune diseases (Chaly et al., 2014; Li et al., 2019).
Inflammatory processes play a pivotal role in the development and progression of depression. Since Follistatin-like protein 1 (FSTL1) has been identified as a novel inflammatory protein, a variety of studies suggest that targeting FSTL1 may be useful in the treatment of diseases in which inflammation plays a central role. In the study, we aimed to investigate the causal relationship between FSTL1 signaling and the development of depression. To explore the effect and mechanism of FSTL1 on chronic stress-induced depression, the chronic unpredictable mild stress (CUMS) paradigm was used. Animals subjected to CUMS for 4 weeks exhibited depressive-like symptoms, including decreased sucrose preference and obvious behavioral despair, concomitantly with increased FSTL1 level in the hippocampus. In contrast, mice with FSTL1 knockdown abolished CUMS induced depression-like and anxiety-like behaviors. Moreover, FSTL1 knockdown reversed CUMS induced synaptic plasticity deficits in the PP-DG pathway of the hippocampus and increased the expression of synaptic associated proteins in the hippocampus of CUMS exposed mice. Microglia activation induced by CUMS paradigm could be significantly inhibited by FSTL1 knockdown. Furthermore, Western blot revealed that FSTL1 knockdown considerably decreased the expression of indicated molecules TLR4/MyD88/NF-κB signaling pathway in CUMS exposed mice. In conclusion, our data implies that FSTL1 may modulate the microglial activation through TLR4/MyD88/NF-κB signaling, which affects depression-like behaviors and synaptic function deficits induced by CUMS in mice. These results suggested that the role of FSTL1 in mediating microglia-related mechanisms in depression may shed light on developing new therapeutic strategies to treat this prevalent disease.
Myostatin: Basic biology to clinical application
2022, Advances in Clinical Chemistry
Myostatin is a member of the transforming growth factor (TGF)-β superfamily. It is expressed by animal and human skeletal muscle cells where it limits muscle growth and promotes protein breakdown. Its effects are influenced by complex mechanisms including transcriptional and epigenetic regulation and modulation by extracellular binding proteins.
Due to its actions in promoting muscle atrophy and cachexia, myostatin has been investigated as a promising therapeutic target to counteract muscle mass loss in experimental models and patients affected by different muscle-wasting conditions. Moreover, growing evidence indicates that myostatin, beyond to regulate skeletal muscle growth, may have a role in many physiologic and pathologic processes, such as obesity, insulin resistance, cardiovascular and chronic kidney disease. In this chapter, we review myostatin biology, including intracellular and extracellular regulatory pathways, and the role of myostatin in modulating physiologic processes, such as muscle growth and aging. Moreover, we discuss the most relevant experimental and clinical evidence supporting the extra-muscle effects of myostatin. Finally, we consider the main strategies developed and tested to inhibit myostatin in clinical trials and discuss the limits and future perspectives of the research on myostatin.
HMEJ-mediated site-specific integration of a myostatin inhibitor increases skeletal muscle mass in porcine
2021, Molecular Therapy Nucleic Acids
As a robust antagonist of myostatin (MSTN), follistatin (FST) is an important regulator of skeletal muscle development, and the delivery of FST to muscle tissue represents a potential therapeutic strategy for muscular dystrophies. The N terminus and FSI domain of FST are the functional domains for MSTN binding. Here, we aimed to achieve site-specific integration of FSI-I-I, including the signal peptide, N terminus, and three FSI domains, into the last codon of the porcine MSTN gene using a homology-mediated end joining (HMEJ)-based strategy mediated by CRISPR-Cas9. Based on somatic cell nuclear transfer (SCNT) technology, we successfully obtained FSI-I-I knockin pigs. H&E staining of longissimus dorsi and gastrocnemius cross-sections showed larger myofiber sizes in FSI-I-I knockin pigs than in controls. Moreover, the Smad and Erk pathways were inhibited, whereas the PI3k/Akt pathway was activated in FSI-I-I knockin pigs. In addition, the levels of MyoD, Myf5, and MyoG transcription were upregulated while that of MRF4 was downregulated in FSI-I-I knockin pigs. These results indicate that the FSI-I-I gene mediates skeletal muscle hypertrophy through an MSTN-related signaling pathway and the expression of myogenic regulatory factors. Overall, FSI-I-I knockin pigs with hypertrophic muscle tissue hold great promise as a therapeutic model for human muscular dystrophies.
Identification of two genes potentially related to myogenesis and muscle growth in Fenneropenaeus chinensis: Activin receptor II and Follistatin-like protein
2021, Gene
Activin receptor (ActR) and follistatin-like (FSTL) genes, which are involved in the Myostatin (Mstn) related TGF-β/Smad signaling pathway, play important roles in regulating the muscle generation, development and growth of muscle in vertebrate. Our previous studies have confirmed that Mstn negatively regulates muscle development and growth in Fenneropenaeus chinensis as that in vertebrate. However, the roles of ActR and FSTL in muscle development and growth in invertebrate remains unclear. In the present study, type II ActR(FcActRII) and FSTL (FcFSTL) genes from F. chinensis were cloned and characterized, and their functions on muscle development and growth were investigated. The full-length cDNAs of FcActRII and FcFSTL were 2366 bp that encoded 572 amino acids and 2474 bp that encoded 717 amino acids, respectively. Sequence analysis revealed that the overall protein sequences of the two genes shared 97% and 96% identities with Penaeus vannamei and 50%-59% and 35%-36% identities with vertebrates, respectively. In the early development stages, muscles firstly appeared in nauplius stage and developed gradually until post larval, and the mRNA expressions of FcActRII increased from gastrula to zoea stage and then decreased from zoea stage to post larval stage while that of FcFSTL was lowest in gastrula stage and increased rapidly in nauplius stage and then expressed stably from nauplius stage to post-larval stage. In the adult shrimp, the two genes were widely distributed in the examined tissues. The FcActRII expression in muscle of L group was significantly lower than that of S group, but the FcFSTL expression showed an opposite result. After down-regulating the expression of FcMstn by RNAi, FcActRII expression was significantly down-regulated while that of FcFSTL was up-regulated. The present study suggested that FcActRII and FcFSTL, regulated by FcMstn, might be involved in myogenesis and muscle growth.
Characterization and expression of the follistatin-related protein gene in golden pompano Trachinotus ovatus larvae
2020, Gene Reports
The follistatin-related protein (FRSP) gene performs numerous functions through binding with cell regulatory proteins in transforming growth factor beta (TGF-β) superfamily such as activin and myostatin. The FRSP gene has been extensively studied in human and other vertebrate models such as chick and mouse to explore its role for disease control and organogenesis. However, very limited information exists on the FRSP gene and its expression during fish ontogeny. In this study, full-length cDNA sequence of the FSRP gene was characterized using next generation sequencing (Illumina HiSeq2000) and mRNA expression was evaluated using qPCR in golden pompano Trachinotus ovatus (Linnaeus 1758) larvae. The FRSP gene was composed of 1500 bp with an open reading frame of 936 bp, encoded 311 amino acids that have molecular weight of 34.55 kDa. The deduced amino acids of the FSRP gene contained a signal peptide, Kazal domain and EF-hand calcium-binding domain. The FSRP gene of T. ovatus has closest identity and similarity with Siniperca chuatsi and Larimichthys rocea. The mRNA expression of the FRSP gene gradually increased from 0 to 2 day post hatch (DPH), reached maximum at 3 DPH, and significantly decreased from 4 DPH to 18 DPH. The mRNA analysis in tissues revealed higher levels of FRSP gene expression in the liver head and eye but lower levels of expression in the kidney, muscles, and head-kidney. This study provides useful information to explore the functional mechanism of FRSP gene in fish ontogeny.
Overcoming neuroendocrine and metabolic barriers to puberty: the role of melatonin in advancing puberty in ewe lambs
2020, Domestic Animal Endocrinology
Citation Excerpt :
It is currently unclear whether this correlation is the result of intramuscular fat distribution, thus increasing leptin concentrations with accumulated muscle, or a combined effect with fluctuating follistatin concentrations [42]. Although increased levels of leptin have a promotional effect on puberty onset [42,97–99,101], follistatin is rather known for its inhibition of FSH, and thus downregulation of the hypothalamic-pituitary-gonadal axis [109–111]. A glycoprotein with multiple paracrine functions, follistatin, binds to the hormone activin, inhibiting FSH and minimizing GnRH receptor activation in the pituitary [110,111].
Pubertal onset in the ewe is subject to a multitude of physiological and environmental constraints. As seasonal breeders, sheep rely on decreasing photoperiod to enter puberty and the subsequent breeding periods, hindering production. The initiation of puberty defines the reproductive yield of the ewe, and as such is a critical factor influencing production outcomes. Currently, the misconception that ovine puberty is reliant on age results in ewes being bred at over a year old, leading to a substantial unproductive period between birth and first conception. As such, transcending pubertal barriers to allow for earlier initiation of reproductive competency has significant commercial merit. The primary candidate to achieve this is the neurohormone melatonin, a key factor that naturally signals photoperiodic change that facilitates seasonal remodeling of the ovine hypothalamic-hypophyseal-gonadal axis. Despite being known to modulate reproductive seasonality in both the mature ewe and ram, the ability of melatonin to advance ewe puberty remains underutilized in industry. To optimize melatonin application and shape perceptions of breeding ewe lambs, a greater understanding of pubertal impediments and the natural role of melatonin is warranted. This review examines the physiological role and applications of melatonin to advance ewe puberty, and how this may act in conjunction with other physiological and metabolic cues.

View all citing articles on Scopus

^☆: Address reprint requests to Dr. David J. Phillips, Institute of Reproduction and Development, Monash Medical Center, Clayton Road, Clayton, Victoria 3168, Australia. Fax: +61 3 9550 3584. E-mail:[email protected].

^☆☆: Burger, H, GFindlay, JRobertson, Dde Kretser, DPetraglia, F

View full text

Regular ArticleFollistatin: A Multifunctional Regulatory Protein☆,☆☆

Abstract

Fertil Steril

Dev Biol

Cell

Biochem Biophys Res Commun

Arch Biochem Biophys

Mol Cell Endocrinol

Mech Dev

Trends Neurosci

Biochem Biophys Res Commun

Dev Biol

Immunity

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

Cell

Cell

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Mol Cell Endocrinol

Mol Cell Endocrinol

Biochem Biophys Res Commun

Cell

Front Neuroendocrinol

Gastroenterology

Hepatology

Exp Cell Res

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Expression of inhibin subunits and follistatin during postimplantation mouse development: Decidual expression of activin and expression of follistatin in primitive streak, somites and hindbrain

Development

Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour

Eur J Biochem

Follistatin inhibits the mesoderm-inducing activity of activin A and the vegetalizing factor from chicken embryo

Roux's Arch Dev Biol

Decay of follicle-stimulating hormone-β messenger RNA in the presence of transcriptional inhibitors and/or inhibin, activin, or follistatin

Mol Endocrinol

Gonadotropin-releasing hormone regulation of pituitary follistatin gene expression during the primary follicle-stimulating hormone surge

Endocrinology

Gonadotropin-releasing hormone regulates follicle-stimulating hormone-β gene expression through an activin/follistatin autocrine or paracrine loop

Endocrinology

Pituitary follistatin regulates activin-mediated production of follicle-stimulating hormone during the rat estrous cycle

Endocrinology

Pituitary follistatin and inhibin subunit messenger ribonucleic acid levels are differentially regulated by local and hormonal factors

Endocrinology

Interleukin-1β regulates pituitary follistatin and inhibin/activin βB

Endocrinology

Activin-A regulates follistatin secretion from cultured rat anterior pituitary cells

Endocrinology

Activin stimulates Sertoli cell proliferation in a defined period of rat testis development

Endocrinology

Expression of mRNA for follistatin and inhibin/activin subunits during follicular growth and atresia

J Mol Endocrinol

Follistatin but not α or βA

J Mol Endocrinol

The role of the rete ovarii in meiosis and follicle formation in the cat, mink and ferret

J Reprod Fertil

Inhibin, activin, and follistatin: Regulation of follicle-stimulating hormone messenger ribonucleic acid levels

Mol Endocrinol

Activin-attenuated expression of transcripts encoding granulosa cell-derived insulin-like growth factor binding proteins 4 and 5 in the rat: A putative antiatretic effect

Biol Reprod

Hormonal regulation of apoptosis in early antral follicles: Follicle-stimulating hormone as a major survival factor

Endocrinology

Depleted level of heparan sulfate proteoglycan in the extracellular matrix of endothelial cell cultures exposed to endotoxin

J Cell Physiol

Pituitary activin receptor subtypes and follistatin gene expression in female rats: Differential regulation by activin and follistatin

Endocrinology

Ectopic expression of SPARC inXenopus

J Histochem Cytochem

Partial charaterization of inhibin, activin and follistatin in the term human placenta

J Clin Endocrinol Metab

Regular Article
Follistatin: A Multifunctional Regulatory Protein☆,☆☆

Interleukin-1β regulates pituitary follistatin and inhibin/activin β_B

Follistatin but not α or β_A