Members of the TGFβ family are critical regulators of cell growth, survival and function and have important roles in development and tissue fate determination. They also have important roles in homeostatic regulation of adult tissues and systems. My lab focuses on the activin/myostatin/GDF11 branch of the TGFb family tree, and this group of hormones is regulated by the extracellular antagonists follistatin (FST) and follistatin like-3 (FSTL3). These two proteins are structurally and biochemically related, bind ligand irreversibly, and regulate the bioactivity of activin, myostatin, and GDF11 in numerous tissues. Research in my lab is concentrated on the roles of these growth factors and their antagonists in two areas, metabolism and reproduction.
To examine the in vivo actions of FSTL3 and FST in adults, we created mice in which the FSTL3 gene was inactivated and found that these mice develop a suite of metabolic phenotypes, including enlarged pancreatic islets, beta cell hyperplasia, improved insulin sensitivity and glucose tolerance, reduced visceral fat, and fatty liver. We have also created mice in which the FST gene was modified so that the circulating FST isoform, FST315 is not synthesized while the FST288 isoform important for development is made normally. These mice are born but are subfertile. We crossed these two mutant strains and the double mutant has insulin resistance and increased adiposity (opposite of FSTL3 KO mouse). Taken together, these mouse models reinforce the concept that regulation of activin, myostatin, and/or GDF11 by FSTL3 and/or FST is critical for normal glucose metabolism in adults.
We are focused the roles of these growth factors and antagonists in pancreatic islet composition and beta cell expansion since the FSTL3 KO mouse had larger islets with more beta cells than WT mice. We found that beta cell proliferation was not enhanced in the FSTL3 KO mice suggesting other mechanisms account for the expanded number of beta cells. Our current research explores the source of these new beta cells with the hope that understanding regulation of beta cell expansion in these mice could lead to new treatments for diabetes in which beta cells fail to produce sufficient insulin to control blood glucose. Preliminary evidence suggests that transdifferentiation of alpha to beta cells may account for a portion of this beta cell expansion.
The FST mutant mice (FST288-only) also have an interesting reproductive phenotype that is similar to human Premature Ovarian Failure (POF) also known as Primary Ovarian Insufficiency (POI). In women with this disorder, the supply of primordial follicles containing dormant oocytes is depleted prematurely leading to menopause before the age of 40. In FST288-only mice, females usually stop breeding between 6-9 months due to a deficit of follicles to ovulate. We identified the source of this defect as the pool of primordial follicles, while initially larger, becomes depleted faster and thus, ovulation terminates. The cause of the larger initial primordial follicle pool and its greater instability are currently under investigation. It is hoped that a better understanding of this process could lead to new therapies for women with POF, or perhaps provide diagnostics or genetic tools for screening women before this disorder exerts its full effects and fertility is lost.
Current activities in the lab are concentrated on deciphering the biochemical, molecular and genetic mechanisms whereby each of these phenotypes are manifested, as well as to further characterize the precise nature and onset of each phenotype to determine their interrelatedness. The results of these studies will lead to new understanding of the role of FSTL3 and FST, as well as the TGFb superfamily ligands they regulate, in maintaining normal glucose metabolism and reproduction in adults and may also provide the basis for development of new pharmaceutical approaches for treating diabetes, insulin resistance and infertility.
We recently founded a biotech company, Fairbanks Pharmaceuticals (Fairbankspharma.com) to determine develop novel therapies for diabetes based on our research with FSTL3 KO mice.
Brown ML, Andrzejewski D, Burnside A, Schneyer AL. Activin Enhances α- to β-cell Transdifferentiation As A Source For β-Cells In Male FSTL3 Knockout Mice. Endocrinology. 2016 Mar;157(3):1043-54. PMID: 26727106.
Andrzejewski D, Brown ML, Ungerleider N, Burnside A, Schneyer AL. 2015. Activins A and B regulate fate-determining gene expression in islet cell lines and islet cells from male mice. Endocrinology. 2015 Jul;156(7):2440-50. doi: 10.1210/en.2015-1167. Epub 2015 May 11. PMID: 25961841. Similar articles Select item 25937185.
Brown ML, Ungerleider N, Bonomi L, Andrzejewski D, Burnside A, Schneyer A. 2014. Effects of activin A on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors. Islets. 2014;6(5-6):e1017226. doi: 10.1080/19382014.2015.1017226. PMID: 25833251.
Ungerleider NA, Bonomi LM, Brown ML, Schneyer AL. 2013. Increased activin bioavailability enhances hepatic insulin sensitivity while inducing hepatic steatosis in male mice. Endocrinology. 154(6):2025-33. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Oldknow KJ, Seebacher J, Goswami T, Villen J, Pitsillides AA, O'Shaughnessy PJ, Gygi SP, Schneyer AL, Mukherjee A. 2013. Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor β (TGFβ) signaling is essential for testicular aging and regulating testis size. Endocrinology. 154(3):1310-20. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Bonomi L, Brown M, Ungerleider N, Muse M, Matzuk MM, Schneyer A. 2012. Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity. Am J Physiol Endocrinol Metab. 303(5):E587-96. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Dunphy KA, Schneyer AL, Hagen MJ, Jerry JD. 2011. The role of activin in mammary gland development and oncogenesis. Journal of mammary gland biology and neoplasia. 16(2):117-26. Google Scholar BibTex Tagged RIS RTF XML.
Dasarathy S, McCullough AJ, Muc S, Schneyer A, Bennett CD, Dodig M, Kalhan SC. 2011. Sarcopenia associated with portosystemic shunting is reversed by follistatin. J Hepatol. 54(5):915-21. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Kimura F, Bonomi LM, Schneyer AL. 2011. Follistatin regulates germ cell nest breakdown and primordial follicle formation. Endocrinology. 152(2):697-706. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Brown ML, Bonomi L, Ungerleider N, Zina J, Kimura F, Mukherjee A, Sidis Y, Schneyer A. 2011. Follistatin and follistatin like-3 differentially regulate adiposity and glucose homeostasis. Obesity (Silver Spring). 19(10):1940-9. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Brown ML, Kimura F, Bonomi LM, Ungerleider NA, Schneyer AL. 2011. Differential synthesis and action of TGFß superfamily ligands in mouse and rat islets. Islets. 3(6):367-75. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Schneyer A. 2011. Getting big on BPA: role for BPA in obesity? Endocrinology. 152(9):3301-3. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Xia Y, Babitt JL, Bouley R, Zhang Y, Da Silva N, Chen S, Zhuang Z, Samad TA, Brenner GJ, Anderson JL et al. 2010. Dragon enhances BMP signaling and increases transepithelial resistance in kidney epithelial cells. J Am Soc Nephrol. 21(4):666-77. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Kimura F, Sidis Y, Bonomi L, Xia Y, Schneyer A. 2010. The follistatin-288 isoform alone is sufficient for survival but not for normal fertility in mice. Endocrinology. 151(3):1310-9. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Stamler R, Keutmann HT, Sidis Y, Kattamuri C, Schneyer A, Thompson TB. 2008. The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity. J Biol Chem. 283(47):32831-8. PubMed Google Scholar BibTex Tagged RIS RTF XML.
Schneyer AL, Sidis Y, Gulati A, Sun JL, Keutmann H, Krasney PA. 2008. Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin. Endocrinology. 149(9):4589-95. PubMed Google Scholar BibTex Tagged RIS RTF XML.