Dr. Schneyer is a senior faculty member of the Reproductive Endocrine Unit at the MGH and Associate Professor of Medicine at Harvard Medical School. His primary roles are in basic and translational research as well as in training both Ph.D. and medical fellows in laboratory and research methods.

Research Interests:

Biochemistry, Physiology, and Pathophysiology of Follistatin and FSTL3.
Follistatin is a 35 kD glycoprotein that was originally discovered in gonadal extracts. Its actions appear to be mediated primarily by its ability to irreversibly bind and neutralize activin, a growth factor in the TGFb superfamily of growth and differentiation factors. Since both activin and follistatins are produced in a wide variety of tissues and at multiple times during development, as well as in adult tissues, it is now accepted that these proteins act primarily via paracrine or autocrine mechanisms to regulate growth and/or differentiation of many cell types.

Our follistatin group has many projects funded mainly by three NIH R01 grants, that range from structure/function relationships between follistatin domains and activin, to cellular and molecular mechanisms whereby follistatin neutralizes activin's actions, to differential biosynthesis and activity of the related Follistatin Like-3 (FSTL3). FSTL3 is a relatively new protein that is structurally closely related to follistatin, and shares many biological actions in vitro. However, there are also important differences, suggesting that in vivo, these two activin-binding proteins have non-overlapping activities. In particular, it seems that FSTL3 binds myostatin, a negative regulator of muscle growth. We have now made FSTL3 knockout mice in which muscle and fat tissues appear to be abnormal, suggesting that modulation of FSTL3 may have important human applications.

Ovarian Follicle Development.
Normal growth and development of ovarian follicles involves a complex orchestration of endocrine acting gonadotropic hormones and a large number of locally active growth and differentiation factors. Among this latter group are members of the TGFb superfamily, including inhibin and activin. Inhibin is a heterodimeric gonadal protein comprised of an a- and a b-subunit with an endocrine role of suppressing FSH synthesis and secretion from the pituitary gland. Activin is a related protein composed of two of inhibin's b-subunits and has the biological activity of increasing FSH secretion from the pituitary, as well as numerous other developmental and growth related functions.

Although the endocrine action of inhibin is now widely accepted, a number of studies indicate potential actions of inhibin and activin within the ovary itself. Our clinical studies on growth of normal follicles compared to those arrested at an early antral stage in women with polycystic ovary syndrome (PCOS) indicate that reduced inhibin production and possibly action are associated with the follicular developmental arrest that is characteristic of patients with this disorder. To experimentally examine this hypothesis, we are pursuing a number of approaches to identify inhibin's signaling pathways and its role in follicular development. These studies include biochemical characterization of inhibin receptors and signaling pathways as well as genetically altered mice with disruptions in the inhibin pathway. In vivo and in vitro analysis of these models is expected to provide new leads into pathways and roles for inhibin and activin in the ovary, and hence, for normal female and male fertility.

Selected Publications:

• Messerlian-Lambert GM, Hall JE, Sluss PM, Taylor AE, Martin KA, Groome NP, Crowley WF Jr, and Schneyer AL. Relatively low levels of dimeric inhibin circulate in men and women with polycystic ovarian syndrome using a specific two-site enzyme-linked immunosorbent assay. J Clin Endocrinol Metab 1994; 79:45-50.

• Schneyer AL, Rzucidlo DA, Sluss PM, and Crowley WF Jr. Characterization of unique binding kinetics of follistatin and activin or inhibin in serum. Endocrinology 1994; 135:667-674.

• Schneyer A, Fujiwara T, Fox J, Welt C, Adams J, Messerlian G, Taylor A. 2000. Dynamic changes in the intrafollicular inhibin/activin/follistatin axis during human follicular development: Relationship to circulating hormone concentrations. J Clin Endo Metab 2000; 85:3319-30.

• Tortoriello DV, Sidis Y, Holtzman DA, Holmes WA, Schneyer AL. Human follistatin-related protein: A structural homologue of follistatin with nuclear localization. Endocrinol 2001; 142:3426-34.

• Fujiwara T, Sidis Y, Welt C, Lambert-Messerlian G, Fox J, Taylor A, Schneyer AL. Dynamics of inhibin subunit and follistatin mRNA during development of normal and PCOS follicles. J Clin Endo Metab 2001; 86:4206-15

• 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; 143:1613-24.

• Schneyer AL, Schoen A, Quigg A, Sidis Y. Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSRL-3/FSRP/FLRG). Endocrinology 2003:144:1671-74.

• Xia Y, Sidis Y, Schneyer A. Overexpression of follistatin-like 3 in gonads causes defects in gonadal development and function in transgenic mice. Mol Endocrinol. 2004 Apr;18(4):979-94. Epub 2004 Jan 22.

• Keutmann HT, Schneyer AL, Sidis Y. The role of follistatin domains in follistatin biological action. Mol Endocrinol. 2004 Jan;18(1):228-40. Epub 2003 Oct 16.

• 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.

• Sidis Y, Schneyer AL, Keutmann HT. Heparin and activin-binding determinants in follistatin and FSTL3. Endocrinology 2004; In Press.

• Del Re E, Sidis Y, Fabrizio DA, Lin HY, Schneyer A. Reconstitution and analysis of soluble inhibin and activin recetor complexes in a cell-free system. J. Biol. Chem 2004; In Press.