Follistatin

FST
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3HH2, 2B0U, 2P6A
Identifiers
Aliases	FST, FS, follistatin
External IDs	OMIM: 136470; MGI: 95586; HomoloGene: 7324; GeneCards: FST; OMA:FST - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q11.2 Start 53,480,626 bp[1] End 53,487,134 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13|13 D2.2 Start 114,588,826 bp[2] End 114,595,487 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium right lobe of liver oocyte secondary oocyte mucosa of urinary bladder Achilles tendon pericardium subcutaneous adipose tissue gastric mucosa saphenous vein Top expressed in cumulus cell primitive streak calvaria ovary dermis seminal vesicula incisor skin of abdomen nasal cavity skin of back More reference expression data BioGPS n/a
Gene ontology Molecular function heparan sulfate proteoglycan binding protein binding signal transducer activity activin binding activin receptor antagonist activity Cellular component extracellular region Biological process positive regulation of hair follicle development negative regulation of activin receptor signaling pathway negative regulation of transcription by RNA polymerase II hematopoietic progenitor cell differentiation signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10468 14313 Ensembl ENSG00000134363 ENSMUSG00000021765 UniProt P19883 P47931 RefSeq (mRNA) NM_006350 NM_013409 NM_008046 NM_001301373 NM_001301375 RefSeq (protein) NP_006341 NP_037541 NP_001288302 NP_001288304 NP_032072 Location (UCSC) Chr 5: 53.48 – 53.49 Mb Chr 13: 114.59 – 114.6 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Follistatin, also known as activin-bindings protein, is a protein that in humans is encoded by the FST gene.^[5][6] Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.^[6]

Its primary function is the binding and bioneutralization of members of the TGF-β superfamily, with a particular focus on activin, a paracrine hormone.

An earlier name for the same protein was FSH-suppressing protein (FSP). At the time of its initial isolation from follicular fluid, it was found to inhibit the anterior pituitary's secretion of follicle-stimulating hormone (FSH).

Biochemistry

Follistatin is part of the inhibin-activin-follistatin axis.

Three isoforms, FS-288, FS-300, and FS-315 have been reported. Two, FS-288 and FS-315, are created by alternative splicing of the primary mRNA transcript. FS-300 (porcine follistatin) is thought to be the product of posttranslational modification via truncation of the C-terminal domain from the primary amino-acid chain.

Although FS is ubiquitous, its highest concentration is in the female ovary, followed by the skin.

Follistatin is produced by folliculostellate (FS) cells of the anterior pituitary. FS cells make numerous contacts with the classical endocrine cells of the anterior pituitary including gonadotrophs.

Function

In the tissues activin has a strong role in cellular proliferation, thereby making follistatin the safeguard against uncontrolled cellular proliferation and also allowing it to function as an instrument of cellular differentiation. These roles are vital in tissue rebuilding and repair, and may account for follistatin's high presence in the skin.

In the blood, activin and follistatin are involved in the inflammatory response following tissue injury or pathogenic incursion. The source of follistatin in circulating blood plasma has yet to be determined, but due to its autocrine nature speculation suggests the endothelial cells lining all blood vessels, or the macrophages and monocytes circulating within the whole blood, may be sources.

Follistatin is involved in embryo development. It has inhibitory action on bone morphogenic proteins (BMPs); BMPs induce the ectoderm to become epidermal ectoderm. Inhibition of BMPs allows neuroectoderm to arise from ectoderm, a process which eventually forms the neural plate. Other inhibitors involved in this process are noggin and chordin.

Follistatin and BMPs are play a role in folliculogenesis within the ovary. The main role of follistatin in the oestrus/menstrus ovary appears to be progression of the follicle from early antral to antral/dominant. It is also involved in the promotion of cellular differentiation of the estrogen producing granulosa cells (GC) of the dominant follicle into the progesterone producing large lutein cells (LLC) of the corpus luteum.

Clinical significance

Follistatin is studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin (also known as GDF-8, a TGF superfamily member) which inhibits excessive muscle growth. Lee and McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in increased muscle mass.^[7][8] In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength.^[9]

Increased levels of follistatin, by leading to increased muscle mass of certain core muscular groups, can increase life expectancy in cases of spinal muscular atrophy (SMA) in animal models.^[10]

Elevated circulating follistatin levels are also associated with increased risk of type 2 diabetes , early death, heart failure, stroke and chronic kidney disease. It has been demonstrated that follistatin contributes to insulin resistance in type 2 diabetes development and nonalcoholic fatty liver disease (NAFLD). The genetic regulation of follistatin secretion from the liver is via Glucokinase regulatory protein (GCKR) identified by large GWAS studies. ^{[11] [12]}

It is also investigated for its involvement in polycystic ovary syndrome (PCOS), in part to resolve debate as to its direct role in this disease.^[13]

Sporadic inclusion body myositis, a variant of inflammatory myopathy, involves muscle weakness. In one clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, walk test results significantly improved versus untreated controls, along with decreased fibrosis and improved regeneration.

ACE-083, a follistatin-based fusion protein, was investigated for treatment focal or asymmetric myopathies. Intramuscular ACE-083 increased growth and force production in injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, without systemic effects or endocrine disruption.^[14]

AAV-mediated FST reduced obesity-induced inflammatory adipokines and cytokines systemically and in synovial fluid. Mice receiving FST therapy were protected from post-traumatic osteoarthritis and bone remodeling from joint injury.^[15]

In another mouse study, high dose animals showed significant quadricep growth.

References

Further reading

External links

• Follistatin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P19883 (Follistatin) at the PDBe-KB.