Follistatin

follistatin
Structure of the follistatin/activin complex based on PDB 2b0u.
Available structures
1lr8, 2p6a, 1lr7, 2arp, 1lr9, 2b0u
Identifiers
Symbols	FST; FS
External IDs	OMIM: 136470 MGI: 95586 HomoloGene: 7324
Gene ontology Molecular function • protein binding • signal transducer activity • binding Cellular component • extracellular region Biological process • keratinocyte proliferation • BMP signaling pathway • odontogenesis of dentine-containing tooth • negative regulation of follicle-stimulating hormone secretion • pattern specification process • female gonad development • negative regulation of transcription from RNA polymerase II promoter • hair follicle morphogenesis • multicellular organismal development • positive regulation of hair follicle development • negative regulation of cell differentiation • gamete generation
Orthologs
Species	Human	Mouse
Entrez	10468	14313
Ensembl	ENSG00000134363	ENSMUSG00000021765
UniProt	P19883	P47931
RefSeq	NM_013409 (mRNA)	NM_008046 (mRNA)
	NP_006341 (protein)	NP_032072 (protein)
Location	Chr 5: 52.81 - 52.82 Mb	Chr 13: 115.24 - 115.25 Mb
PubMed search	[1]	[2]

Follistatin is a single chain autocrine glycoprotein found to be ubiquitous within the body of nearly all higher animals, that is the product of a single gene.

It was initially isolated from follicular fluid and was identified as a protein fraction that inhibited Follicle-stimulating hormone (FSH) secretion from the anterior pituitary, and so was known as FSH-suppressing protein (FSP). Since then its primary function has been determined to be the binding and bioneutralization agent of members of the TGF-beta superfamily, with primary focus on Activin, a paracrine hormone (TGF-b member) which enhances secretion of FSH in the anterior pituitary.

Biochemistry

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

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

Although FS is ubiquitous its highest concentration has been found to be in the female ovary, followed by the skin.

The activin-binding protein 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.

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. Both of 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 both known to be 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 also circulating within the whole blood, may be sources.

Follistatin is involved in the development of the embryo. 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 also known to play a role in folliculogenesis within the ovary. The main role of follistatin in the oestrus/menstrus ovary, so far, appears to be progression of the follicle from early antral to antral/dominant, and importantly the promotion of cellular differentiation of the oestrogen producing granulosa cells (GC) of the dominant follicle into the progesterone producing large lutein cells (LLC) of the corpus luteum.

Clinical significance

Follistatin is being studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin (aka GDF-8, a TGF superfamily member) which inhibits excessive muscle growth. Lee & McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in greatly increased muscle mass. ^[1][2] In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength. This research paves the way for human clinical trials, which are hoped to begin in the summer of 2010 on Inclusion body myositis.^[3]

A study has also shown that 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. ^[4]

It is also being investigated for its involvement in polycystic ovary syndrome (PCOS), though there is debate as to its direct role in this infertility disease.

References

Further reading

External links

• MeSH Follistatin

v • d • e PDB Gallery 1lr8: Crystal structure of Fs1, the heparin-binding domain of follistatin, complexed with the heparin analogue D-myo-inositol hexasulphate (Ins6S)   2p6a: The structure of the Activin:Follistatin 315 complex   1lr7: Crystal structure of Fs1, the heparin-binding domain of follistatin, complexed with the heparin analogue sucrose octasulphate (SOS)   2arp: Activin A in complex with Fs12 fragment of follistatin   1lr9: STRUCTURE OF Fs1, THE HEPARIN-BINDING DOMAIN OF FOLLISTATIN   2b0u: The Structure of the Follistatin:Activin Complex

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