Research Interests: Pathways to Breast Cancer Prevention and Treatment
Members of the TGFβ family are critical regulators of cell growth, survival, and function and have important roles in tissue development and differentiation. They are regulated extracellularly by binding proteins that either neutralize their activity or establish gradients of activity during development. Research in my laboratory is focused on follistatin (FST) and follistatin-like 3 (FSTL3), proteins that bind and neutralize related members of the TGFβ superfamily, including activin, myostatin, and GDF11. Activities of these factors in adults are largely unexplored. Previous studies in our lab have established biochemical and molecular requisites for the irreversible binding of activin by FST and FSTL3 and have defined biochemical features of the FST isoforms that govern their differential in vivo actions.
To further examine the in vivo actions of FSTL3 and FST in adults, we created mice in which the FSTL3 gene was deactivated. We discovered that their fertility was largely unaffected, despite high expression of FSTL3 in testis and placenta. However, these mice developed a suite of metabolic phenotypes, including enlarged pancreatic islets, &beta-cell hyperplasia, improved insulin sensitivity and glucose tolerance, reduced visceral fat, and a fatty liver. We have also created mice in which the FST gene was modified so the circulating isoform (FST315) was not synthesized while the FST288 isoform important for development was made normally. These mice are subfertile, have premature ovarian failure, and have some of the metabolic phenotypes seen in the mice with deactivated FSTL3. 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 and reproduction in adults. Double-mutant mice have increased fat mass and decreased lean mass.
Current activities in the lab are concentrated on deciphering the biochemical, molecular, and genetic mechanisms whereby each of these phenotypes is manifested, as well as further characterizing the precise nature and onset of each phenotype to determine their interrelatedness. The results of these studies will lead to a new understanding of the role of FSTL3 and FST, as well as the ligands they regulate, in maintaining normal glucose metabolism and reproduction in adults. They may also provide the basis for development of new pharmaceutical approaches for treating diabetes and insulin resistance.
A new direction for the lab is to explore the role of neonatal exposure to endocrine disruptors such as BPA in causing adult reproductive and metabolic disease.
Our laboratory has also contributed to the understanding of the roles and molecular mechanisms whereby activin, inhibin, follistatin, and FSTL3 act to regulate normal reproductive processes, as well as how they contribute to reproductive disease. Our goal is to decipher the role of activin, and its regulation by follistatin and FSTL3, on development of ovarian follicles during embryogenesis and neonatal life. We are also exploring how endocrine disruptors-chemicals in the environment that alter normal endocrine systems-contribute to infertility. The modified follistatin mice described above have altered follicle formation and development, leading to a form of infertility resembling human primary ovarian insufficiency, in which reproduction ceases before the onset of normal menopause. These models allow us to explore possible mechanisms for the human disorder and to test new treatments for this condition that might help patients with this disease.
Center for Endocrine and Metabolic Research (Director)
Center of Excellence in Apoptosis Research
Brown M, Kimura F, Bonomi L, Ungerleider N, Schneyer A. Myostatin enhances insulin secretion from rats but not mouse islets: species specific expression and action of TGF-β superfamily ligands. J Endocrinol. Revised manuscript submitted (2011).
Brown ML, Bonomi L, Ungerleider N, Zina J, Kimura F, Mukherjee A, Sidis Y, Schneyer A. Follistatin and Follistatin Like 3 Differentially Regulate Adiposity and Glucose Homeostasis. Obesity (2011). ePublished ahead of print
Schneyer A, Brown M. Altered glucose homeostasis resulting from developmental exposures to endocrine disruptors. In: Diamanti-Kandarakis D, Gore AC, eds. Endocrine Disruptors and Puberty. New York, NY: Springer/Humana; in press.
Kimura F, Bonomi L, Schneyer A. Follistatin regulates germ cell nest breakdown and primordial follicle formation. Endocrinology. In press.
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;151:1310-1319.
Dasarathy S, McCullough AJ, Muc S, Schneyer A, et al. Sarcopenia associated with portosystemic shunting is reversed by follistatin [published online ahead of print October 25, 2010]. J Hepatol. PMID: 21145817.
Brown ME, Schneyer AL. Emerging role for TGFβ superfamily in &beta-Cell homeostasis. Trends Endocrinol Metab. 2010;21(7):441-448.
Schneyer A, Xia Y. The biology of activin: recent advances in structure, regulation and function. J Endocrinol. 2009;202:1-12.
Schneyer AL, Sidis Y, Gulati A, Sun JL, Keutmann H, Krasney PA. Differential antagonism of activin, myostatin and GDF11 by wild type and mutant follistatin. Endocrinology. 2008;149:4589-4595.
Stamler R, Ketumann HT, Sidis Y, Kattamuri C, Schneyer A, Thompson TB. The structure of FSTL3.activin complex: differential binding of N-terminal domains influences follistatin-type antagonist activity. J Biol Chem. 2008;283:32831-32838.
Xia Y, Yu PB, Sidis Y, Beppu H, Bloch KD, Schneyer AL, Lin HY. Repulsive guidance molecule (RGMa) alters utilization of bone morphogenetic protein (BMP) type II receptors by BMP2 and BMP4. J Biol Chem. 2007;282:18129-18140.
Lambert-Messerlian G, Eklund E, Pinar H, Tantavahi U, Schneyer AL. Activin subunit and receptor expression in normal and cleft human fetal palate tissues. Pediatr Dev Pathol. 2007;22:1-7.
Mukherjee A, Sidis Y, Mahan A, Raher MJ, Xia Y, Rosen ED, Bloch K, Thomas MK, Schneyer AL. FSTL3 deletion reveals roles for TGFβ family ligands in glucose and fat homeostasis in adults. Proc Nat Acad Sci. 2007;104:1348-1353.
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;147:3586-3597.
Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nature Genetics. 2006;38:531-539.
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):5052-5062.
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):5582-5587.
Babitt JL, Zhang Y, Samad TA, Xia Y, Tang J, Campagna JA, Schneyer AL, et al. Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem. 2005;280(33):29820-29827.
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):3614-3621.
Samad TA, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong SJ, Campagna JA, Perusini S, Fabrizio DA, Schneyer AL, et al. DRAGON, a bone morphogenetic protein co-receptor. J Biol Chem. 2005;280(14):14122-14129.
Sidis Y, Schneyer AL, Keutmann HT. Heparin and activin-binding determinants in follistatin and FSTL3. Endocrinology. 2005;146(1):130-136.
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):53126-53135.
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;89:5067-5075.
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 development and function in transgenic mice. Molec Endocrinol. 2004;18:979-994.
Chair, Endocrine Society Task Force on NIH Affairs
Member, NIH Affairs Subcommittee of FASEB's Science Policy Committee