HGNC Approved Gene Symbol: FST
Cytogenetic location: 5q11.2 Genomic coordinates (GRCh38) : 5:53,480,629-53,487,134 (from NCBI)
Follistatin is an important regulator of activin (see 147290) and other members of the TGF-beta (see 190180) superfamily (Schneyer et al., 2004).
Ueno et al. (1987) isolated from porcine ovarian follicular fluid a peptide with follicle-stimulating hormone (136530) release inhibitory activity. The molecule, which they designated follistatin, was found to be highly enriched in cysteines and to be composed of a single polypeptide chain. It had no sequence homology with the previously characterized follicular fluid inhibins (e.g., INHBA; 147290), which are heterodimeric proteins.
By Northern blot analysis, Tortoriello et al. (2001) found follistatin mRNA expressed in nearly all human tissues examined, with highest expression in adult ovary, pituitary, and kidney, and in fetal heart and liver. Immunolocalization of FST in primary cultures of luteinized granulosa cells revealed wide cytoplasmic distribution.
By immunohistochemical staining of human palatal tissue sections, Cox et al. (2019) observed coexpression of FST and its target GDF11 (603936) in the palatal epithelium, including the medial epithelial seam, as well as throughout the palatal and tongue mesenchyme.
By FISH, Bondestam et al. (1999) mapped the FST gene to chromosome 5q11.2.
Hashimoto et al. (1992) showed that activin A (147290) had a mitogenic effect on mouse osteoblastic cells and suppressed their alkaline phosphatase activity. Both mouse and human osteoblastic cell lines secreted follistatin, which inhibited the activity of activin A. Northern blot analysis showed that retinoic acid treatment downregulated follistatin expression. Hashimoto et al. (1992) concluded that follistatin is a negative regulator of activin A.
Schneyer et al. (2004) reviewed the differential actions of FST and FSTL3 (605343). They noted that both FST and FSTL3 bind and inhibit activin B (147390) less efficiently than activin A.
Using DNA microarrays to examine gene expression patterns in normal human placenta, Sood et al. (2006) found elevated expression of follistatin in umbilical cord. This finding was unexpected as follistatin was believed to be synthesized in placental villi and membranes. Follistatin is a direct inhibitor of activin and BMPs (see 112264), which regulate differentiation of progenitor cell types, including hematopoietic cells. Sood et al. (2006) suggested that follistatin may have a role in regulating stem cell renewal versus differentiation in umbilical cord.
Using yeast 2-hybrid and in vitro protein-binding assays, Gao et al. (2007) showed that FST bound angiogenin (ANG; 105850), an angiogenesis-inducing protein. When expressed individually, fluorescence-tagged FST and ANG showed diffuse nuclear localization in transfected HeLa cells. However, when FST and ANG were expressed together, they colocalized in a punctate distribution within nuclei. Mutation analysis showed that domains 2 and 3 of FST were required for ANG binding.
Follistatin, an activin (see 147290)-binding protein and activin antagonist in vitro, can bind to heparan sulfate proteoglycans (e.g., 142460) and may function in vivo to present activins to their receptors. In the mouse, follistatin mRNA is first detected in the deciduum (on embryonic day 5.5), and later in the developing hindbrain, somites, vibrissae, teeth, epidermis, and muscle. Matzuk et al. (1995) used loss-of-function mutant mice to investigate the function of follistatin in mammals. Matzuk et al. (1995) found that follistatin-deficient mice are retarded in their growth, have decreased mass of diaphragm and intercostal muscles, shiny taut skin, skeletal defects of the hard palate and the thirteenth pair of ribs, and abnormal whisker and tooth development. They fail to breathe, and die within hours of birth. These defects are more widespread than those seen in activin-deficient mutant mice, indicating that follistatin may modulate the actions of several members of the TGF-beta family (e.g., 190180).
To investigate the role of follistatin during tooth development, Wang et al. (2004) analyzed the tooth phenotypes of follistatin knockout mice and of transgenic mice overexpressing follistatin. Overexpression of Fst in the dental epithelium inhibited ameloblast differentiation in transgenic mouse incisors, whereas in Fst knockout mice, ameloblasts differentiated ectopically on the lingual enamel-free surface. In wildtype mice, Fst was continuously expressed in the lingual dental epithelium but downregulated in the labial epithelium. Experiments on cultured tooth explants indicated that Fst inhibits the ameloblast-inducing activity of bone morphogenetic protein-4 (BMP4; 112262) from the underlying mesenchymal odontoblasts and that Fst expression is induced by activin from the surrounding dental follicle. Wang et al. (2004) concluded that ameloblast differentiation is regulated by antagonistic actions of BMP4 and activin A from 2 mesenchymal cell layers flanking the dental epithelium, and that asymmetrically expressed follistatin regulates the labial-lingual patterning of enamel formation. Wang et al. (2004) suggested that mutations in components of the BMP pathway may account for some cases of amelogenesis imperfecta (see 104500).
Jones et al. (2007) showed that lipopolysaccharide (LPS) challenge in mice resulted in a rapid increase in activin levels through activation of Tlr4 (603030) and Myd88 (602170). Treatment with the activin-binding protein follistatin reduced Tnf (191160) and Il6 (147620) levels and increased Il1b (147720) levels after LPS stimulation. Administration of Fst to mice before challenge with a lethal dose of LPS significantly increased survival, and serum activin A levels were higher in mice that succumbed compared with those that survived. Jones et al. (2007) concluded that activin A has an important role in the inflammatory response and that FST may have significant therapeutic potential to reduce the severity of inflammatory diseases.
Spinal muscular atrophy (SMA; 253300), a common genetic cause of infant mortality, is caused by loss of functional SMN1 (600354), resulting in death of spinal motor neurons. Myostatin (601788), a member of the TGF-beta superfamily, is a potent negative regulator of skeletal muscle mass. Follistatin is a natural antagonist of myostatin, and overexpression of follistatin in mouse muscle leads to profound increases in skeletal muscle mass. Rose et al. (2009) administered recombinant follistatin to an SMA mouse model. Treated animals exhibited increased mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, gross motor function improvement, and mean life span extension by 30%, by preventing some of the early deaths, when compared with control animals. SMN protein levels in spinal cord and muscle were unchanged in follistatin-treated SMA mice, suggesting that follistatin may exert its effect in an SMN-independent manner. Reversing muscle atrophy associated with SMA may represent an unexploited therapeutic target for the treatment of SMA.
For discussion of a possible association between variation in the FST gene and cleft lip/palate, see 136470.0001.
This variant is classified as a variant of unknown significance because its contribution to orofacial clefting (see 119530) has not been confirmed.
In a cohort of 72 families with orofacial clefting from the United States, Colombia, and Australia, Cox et al. (2019) performed exome sequencing and identified a father and 2 daughters (family 22) with cleft lip and palate who were heterozygous for a c.167G-A transition (c.167G-A, NM_013409.2) in the FST gene, resulting in a cys56-to-tyr (C56Y) substitution at a highly conserved residue within the 63-residue N-terminal domain. The mutation was not found in the unaffected paternal grandmother or in the gnomAD database. Functional analysis in transfected HEK293T cells, using a stable cell line sensitive to stimulation by the FST downstream target GDF11 (603936), demonstrated that wildtype FST efficiently and completely antagonized GDF11-stimulated reporter activity. In contrast, the C56Y mutant did not significantly inhibit the stimulation of reporter activity, regardless of the amount of mutant vector transfected.
Bondestam, J., Horelli-Kuitunen, N., Hilden, K., Ritvos, O., Aaltonen, J. Assignment of ACVR2 and ACVR2B the human activin receptor type II and IIB genes to chromosome bands 2q22.2-q23.3 and 3p22 and the human follistatin gene (FST) to chromosome 5q11.2 by FISH. Cytogenet. Cell Genet. 87: 219-220, 1999. [PubMed: 10702675] [Full Text: https://doi.org/10.1159/000015429]
Cox, T. C., Lidral, A. C., McCoy, J. C., Liu, H., Cox, L. L., Zhu, Y., Anderson, R. D., Moreno Uribe, L. M., Anand, D., Deng, M., Richter, C. T., Nidey, N. L., and 18 others. Mutations in GDF11 and the extracellular antagonist, follistatin, as a likely cause of mendelian forms of orofacial clefting in humans. Hum. Mutat. 40: 1813-1825, 2019. [PubMed: 31215115] [Full Text: https://doi.org/10.1002/humu.23793]
Gao, X., Hu, H., Zhu, J., Xu, Z. Identification and characterization of follistatin as a novel angiogenin-binding protein. FEBS Lett. 581: 5505-5510, 2007. [PubMed: 17991437] [Full Text: https://doi.org/10.1016/j.febslet.2007.10.059]
Hashimoto, M., Shoda, A., Inoue, S., Yamada, R., Kondo, T., Sakurai, T., Ueno, N., Muramatsu, M. Functional regulation of osteoblastic cells by the interaction of activin-A with follistatin. J. Biol. Chem. 267: 4999-5004, 1992. [PubMed: 1537876]
Jones, K. L., Mansell, A., Patella, S., Scott, B. J., Hedger, M. P., de Kretser, D. M., Phillips, D. J. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc. Nat. Acad. Sci. 104: 16239-16244, 2007. [PubMed: 17911255] [Full Text: https://doi.org/10.1073/pnas.0705971104]
Matzuk, M. M., Lu, N., Vogel, H., Sellheyer, K., Roop, D. R., Bradley, A. Multiple defects and perinatal death in mice deficient in follistatin. Nature 374: 360-363, 1995. [PubMed: 7885475] [Full Text: https://doi.org/10.1038/374360a0]
Rose, F. F., Jr., Mattis, V. B., Rindt, H., Lorson, C. L. Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy. Hum. Molec. Genet. 18: 997-1005, 2009. [PubMed: 19074460] [Full Text: https://doi.org/10.1093/hmg/ddn426]
Schneyer, A., Sidis, Y., Xia, Y., Saito, S., del Re, E., Lin, H. Y., Keutmann, H. Differential actions of follistatin and follistatin-like 3. Molec. Cell. Endocr. 225: 25-28, 2004. [PubMed: 15451564] [Full Text: https://doi.org/10.1016/j.mce.2004.02.009]
Sood, R., Zehnder, J. L., Druzin, M. L., Brown, P. O. Gene expression patterns in human placenta. Proc. Nat. Acad. Sci. 103: 5478-5483, 2006. [PubMed: 16567644] [Full Text: https://doi.org/10.1073/pnas.0508035103]
Tortoriello, D. V., Sidis, Y., Holtzman, D. A., Holmes, W. E., Schneyer, A. L. Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. Endocrinology 142: 3426-3434, 2001. [PubMed: 11459787] [Full Text: https://doi.org/10.1210/endo.142.8.8319]
Ueno, N., Ling, N., Ying, S.-Y., Esch, F., Shimasaki, S., Guillemin, R. Isolation and partial characterization of follistatin: a single-chain M(r) 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone. Proc. Nat. Acad. Sci. 84: 8282-8286, 1987. [PubMed: 3120188] [Full Text: https://doi.org/10.1073/pnas.84.23.8282]
Wang, X.-P., Suomalainen, M., Jorgez, C. J., Matzuk, M. M., Werner, S., Thesleff, I. Follistatin regulates enamel patterning in mouse incisors by asymmetrically inhibiting BMP signaling and ameloblast differentiation. Dev. Cell 7: 719-730, 2004. [PubMed: 15525533] [Full Text: https://doi.org/10.1016/j.devcel.2004.09.012]