Follistatin Information & Follistatin Links at HealthHaven.com

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 GeneCards: FST Gene
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

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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.

[edit] 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.

[edit] 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.

[edit] References

^ Lee SJ, McPherron AC (2001). "Regulation of myostatin activity and muscle growth". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 9306–11. doi:10.1073/pnas.151270098. PMID 11459935. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11459935.
^ "'Mighty mice' made mightier". http://www.eurekalert.org/pub_releases/2007-08/jhmi-mm082407.php. Retrieved 2008-02-26.
^ "Success Boosting Monkey Muscle Could Help Humans" (in English). 11 Nov 2009. http://www.npr.org/templates/story/story.php?storyId=120316010. Retrieved 2009-11-12.
^ Rose FF, Mattis VB, Rindt H, Lorson CL (December 2008). "Delivery of recombinant follistatin lessens disease severity in a mouse model of Spinal Muscular Atrophy". Hum. Mol. Genet. 18: 997. doi:10.1093/hmg/ddn426. PMID 19074460.

[edit] Further reading

Thompson TB, Lerch TF, Cook RW, et al. (2005). "The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding.". Dev. Cell 9 (4): 535-43. doi:10.1016/j.devcel.2005.09.008. PMID 16198295.
Nakatani M, Takehara Y, Sugino H, et al. (2008). "Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice.". FASEB J. 22 (2): 477-87. doi:10.1096/fj.07-8673com. PMID 17893249.
Lambert-Messerlian G, Eklund E, Pinar H, et al.. "Activin subunit and receptor expression in normal and cleft human fetal palate tissues.". Pediatr. Dev. Pathol. 10 (6): 436-45. doi:10.2350/06-05-0087.1. PMID 18001154.
Walsh S, Metter EJ, Ferrucci L, Roth SM (2007). "Activin-type II receptor B (ACVR2B) and follistatin haplotype associations with muscle mass and strength in humans.". J. Appl. Physiol. 102 (6): 2142-8. doi:10.1152/japplphysiol.01322.2006. PMID 17347381.
Ogino H, Yano S, Kakiuchi S, et al. (2008). "Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice.". Clin. Cancer Res. 14 (3): 660-7. doi:10.1158/1078-0432.CCR-07-1221. PMID 18245525.
Reis FM, Nascimento LL, Tsigkou A, et al. (2007). "Activin A and follistatin in menstrual blood: low concentrations in women with dysfunctional uterine bleeding.". Reprod Sci 14 (4): 383-9. doi:10.1177/1933719107303985. PMID 17644811.
Yerges LM, Klei L, Cauley JA, et al. (2009). "A High-Density Association Study of 383 Candidate Genes for Volumetric Bone Density at the Femoral Neck and Lumbar Spine among Older Men.". J. Bone Miner. Res.: HASH(0x14c4c40). doi:10.1359/jbmr.090524. PMID 19453261.
Blount AL, Vaughan JM, Vale WW, Bilezikjian LM (2008). "A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene.". J. Biol. Chem. 283 (11): 7016-26. doi:10.1074/jbc.M709502200. PMID 18184649.
Eichberger T, Kaser A, Pixner C, et al. (2008). "GLI2-specific transcriptional activation of the bone morphogenetic protein/activin antagonist follistatin in human epidermal cells.". J. Biol. Chem. 283 (18): 12426-37. doi:10.1074/jbc.M707117200. PMID 18319260.
Jones MR, Wilson SG, Mullin BH, et al. (2007). "Polymorphism of the follistatin gene in polycystic ovary syndrome.". Mol. Hum. Reprod. 13 (4): 237-41. doi:10.1093/molehr/gal120. PMID 17284512.
Torres PB, Florio P, Ferreira MC, et al. (2007). "Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis.". Fertil. Steril. 88 (1): 200-5. doi:10.1016/j.fertnstert.2006.11.105. PMID 17296189.
Sidis Y, Mukherjee A, Keutmann H, et al. (2006). "Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins.". Endocrinology 147 (7): 3586-97. doi:10.1210/en.2006-0089. PMID 16627583.
Grusch M, Drucker C, Peter-VÃ¶rÃ¶smarty B, et al. (2006). "Deregulation of the activin/follistatin system in hepatocarcinogenesis.". J. Hepatol. 45 (5): 673-80. doi:10.1016/j.jhep.2006.06.014. PMID 16935389.
Chen M, Sinha M, Luxon BA, et al. (2009). "Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin.". J. Biol. Chem. 284 (3): 1484-94. doi:10.1074/jbc.M803997200. PMID 19011242.
Blount AL, Schmidt K, Justice NJ, et al. (2009). "FoxL2 and Smad3 coordinately regulate follistatin gene transcription.". J. Biol. Chem. 284 (12): 7631-45. doi:10.1074/jbc.M806676200. PMID 19106105.
Phillips DJ, de Kretser DM (1998). "Follistatin: a multifunctional regulatory protein.". Frontiers in neuroendocrinology 19 (4): 287-322. doi:10.1006/frne.1998.0169. PMID 9799587.
Chang SY, Kang HY, Lan KC, et al.. "Expression of inhibin-activin subunits, follistatin and smads in granulosa-luteal cells collected at oocyte retrieval.". J. Assist. Reprod. Genet. 23 (9-10): 385-92. doi:10.1007/s10815-006-9068-7. PMID 17053951.
Kostek MA, Angelopoulos TJ, Clarkson PM, et al. (2009). "Myostatin and follistatin polymorphisms interact with muscle phenotypes and ethnicity.". Medicine and science in sports and exercise 41 (5): 1063-71. doi:10.1249/MSS.0b013e3181930337. PMID 19346981.
Flanagan JN, Linder K, Mejhert N, et al. (2009). "Role of follistatin in promoting adipogenesis in women.". J. Clin. Endocrinol. Metab. 94 (8): 3003-9. doi:10.1210/jc.2008-2005. PMID 19470636.
Peng C, Ohno T, Khorasheh S, Leung PC. "Activin and follistatin as local regulators in the human ovary.". Biol. Signals 5 (2): 81-9. PMID 8836491.