Alan Schneyer

Adjunct Professor, Department of Biology, University of Massachusetts
Professor of Medicine, Tufts School of Medicine

Email: schneyer@cns.umass.edu

Ph.D.: University of Miami
Postdoc: Albany Medical College

New Regulators of Glucose Homeostasis and Insulin Sensitivity

Members of the TGFβ family are critical regulators of cell growth, survival and function and have important roles in development and tissue fate determination. My lab focuses on the activin/myostatin/GDF11 branch of the TGFβ family tree, and this group of hormones is regulated by the extracellular anagonists follistatin (FST) and follistatin like-3 (FSTL3). These antagonists 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, β-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 subfertile with some metabolic phenotypes. The double mutant mouse is different still, with insulin resistance and increased adiposity. Taken together, these two 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 also interested in the roles of these growth factors and antagonists on pancreatic islet composition and β-cell expansion since the FSTL3 KO mouse had larger islets with more β-cells than WT mice. Our current research explores the source of these new β-cells with the hope that understanding regulation of β-cell expansion in these mice could lead to new treatments for diabetes.

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). FST288-only females usually stop breeding between 6-9 months due to a deficit of primordial follicles. We identified the source of this defect as the pool of primordial follicles, which is initially larger but becomes depleted faster. The cause of the larger initial primordial follicle pool and its greater instability are currently under investigation.

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 interrelattedness. The results of these studies will lead to new understanding of the role FSTL3 and FST, as well as the TGFβ superfamily ligands they regulate, in maintaining normal glucose meetabolism and reproduction in adults and also provide the basis for development of new pharmaceutical approaches for treating diabetes, insulin resistance and infertility.

Representative publications:

Schneyer A. Getting big on BPA: role for BPA in obesity? Endocrinology. 2011 Sep;152(9):3301-3.

Brown M, Kimura F, Bonomi L, Ungerleider N, Schneyer A. Differential synthesis and action of TGFb superfamily ligands in mouse and rat islets. Islets. 2011. Nov/Dec;3(6):1-9.

Brown M, Bonomi L, Kimura F, Ungerleider N, Schneyer A. Follistatin And Follistatin Like-3 Differentially Regulate Adiposity And Glucose Homeostasis. Obesity (Silver Spring) 2011 Oct;19(10):1940-9.

Dunphy KA, Schneyer AL, Hagen MJ, Jerry DJ. The role of activin in mammary gland development and oncogenesis. J Mammary Gland Biol Neoplasia. 2011 Jun;16(2):117-26. Epub 2011 Apr 8. PubMed PMID: 21475961.

Dasarathy S, McCullough AJ, Muc S, Schneyer A, Bennett CD, Dodig M, Kalhan SC. Sarcopenia associated with portosystemic shunting is reversed by follistatin. J Hepatol. 2011; 54:915-21. PMID: 21145817.

Kimura F, Bonomi L, Y, Schneyer A. Follistatin Regulates Germ Cell Nest Breakdown And Primordial Follicle Formation. Endocrinology; 2011; 152:697-706. PMID: 21106872.

Xia Y, Babitt JL, Bouley R, Zhang Y, Silva ND, Chen S, Zhuang Z, Samad TA, Brenner GJ, Anderson JL, Hong CC, Schneyer A, Brown D, Lin HY. Dragon Enhances BMP Signaling and Increases Transepithelial Resistance in Kidney Epithelial Cells. J Am Soc Nephrol. 2010; 21:666-77; PMID: 20167703.

Kimura F, Sidis Y, Bonomi L, Xia Y, Schneyer A, The Follistatin-288 (FST288) Isoform Alone is Sufficient For Survival But Not For Normal Fertility In Mice. Endocrinology, 2010; 151:1310-9. PMID: 20032047.

Stamler R, Ketumann HT, Sidis Y, Kattamuri C, Schneyer A, and Thompson TB. The structure of FSTL3:Activin complex: Differential binding of N-terminal domains influences follistatin-type antagonist activity. J Biol Chem 2008: 283:32831-8, PMID 18768470.

Schneyer AL, Sidis Y, Gulati A, Sun JL, Keutmann H and Krasney PA. Differential Antagonism of Activin, Myostatin and GDF11 by Wild Type and Mutant Follistatin. Endocrinology, 2008; 149:4589-95.

Mukherjee A, Sidis Y, Mahan A, Raher MJ, Xia Y, Rosen ED, Bloch K, Thomas MK, and Schneyer AL. FSTL3 deletion reveals roles for TGF family ligands in glucose and fat homeostasis in adults. Proc Nat Acad Sci; 2007; 104:1348-53.

Sidis Y, Mukherjee A, Keutmann HK, Delbaere A, Sadatsuki M, Schneyer A. Biological activity of follistatin isoforms and follistatin like-3 are dependent on differential cell surface binding and specificity for activin, myostatin and BMP's. Endocrinology. 2006;147:3586-97.

Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf J, Andrews NC, Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nature Genetics. 2006;38:531-9.

Saito S, Sidis Y, Mukherjee A, Xia Y, Schneyer A. Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3. Endocrinology. 2005;146(12):5052-62.

Welt CK, Taylor AE, Fox J, Messerlian GM, Adams JM, Schneyer AL. Follicular arrest in polycystic ovary syndrome is associated with deficient inhibin A and B biosynthesis. J Clin Endocrinol Metab. 2005;90(10):5582-7.

Babitt JL, Zhang Y, Samad TA, Xia Y, Tang J, Campagna JA, Schneyer AL, Woolf CJ, Lin HY. Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem. 2005;280(33):29820-7.

Xia Y, Sidis Y, Mukherjee A, Samad TA, Brenner G, Woolf CJ, Lin HY, Schneyer A. Localization and action of Dragon (repulsive guidance molecule b), a novel bone morphogenetic protein coreceptor, throughout the reproductive axis. . Endocrinology. 2005;146(8):3614-21.

Samad TA, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong SJ, Campagna JA, Perusini S, Fabrizio DA, Schneyer AL, Lin HY, Brivanlou AH, Attisano L, Woolf CJ. DRAGON, a bone morphogenetic protein co-receptor. J Biol Chem. 2005;280(14):14122-9.

Sidis Y, Schneyer AL, Keutmann HT. Heparin and activin-binding determinants in follistatin and FSTL3. . Endocrinology. 2005;146(1):130-6.

Del Re E, Sidis Y, Fabrizio DA, Lin HY, Schneyer A. Reconstitution and analysis of soluble inhibin and activin receptor complexes in a cell-free system. J Biol Chem. 2004;279(51):53126-35.

Schneyer AL, Wang Q, Sidis Y, Sluss PM. Differential distribution of follistatin isoforms: Application of a new FS315-specific immunoassay. J Clin Endocrinol Metab. 2004;89:5067-75.

Keutmann HT, Schneyer, A, Sidis Y. The role of follistatin domains in follistatin biological action. Molec Endocrinol. 2004;18:228-240.

Xia Y, Sidis Y, Schneyer A. Overexpression of follistatin like-3 (FSTL3) in gonads causes defects in gonadal develoment and function in transgenic mice. Molec Endocrinol. 2004;18:979-94.

Del Re E, Babitt JL, Pirani A, Schneyer A, Lin HY. In the absence of type III receptor, the TGF type II-B receptor requires the type I receptor to bind TGF2. J Biol Chemistry. 2004;279:22765-72.

Sidis Y, Tortoriello DV, Holmes WE, Pan Y, Keutmann HT, Schneyer AL. Follistatin-related protein and follistatin differentially neutralize endogenous vs. exogenous activin. Endocrinology. 2002;143(5):1613-24.

Fujiwara T, Sidis Y, Welt C, Lambert-Messerlian G, Fox J, Taylor A, Schneyer A. Dynamics of inhibin subunit and follistatin mRNA during development of normal and polycystic ovary syndrome follicles. J Clin Endocrinol Metab. 2001;86(9):4206-15.

Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL. Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. Endocrinology. 2001;142(8):3426-34.

Sidis Y, Schneyer AL, Sluss PM, Johnson LN, Keutmann HT. Follistatin: essential role for the N-terminal domain in activin binding and neutralization. J Biol Chem. 2001;276(21):17718-26.

Welt CK, Schneyer AL. Differential regulation of inhibin B and inhibin a by follicle stimulating hormone and local growth factors in human granulosa cells from small antral follicles. J Clin Endocrinol Metab. 2001;86(1):330-6.