Alan L. Schneyer
Alan L. Schneyer, Ph.D.
Research Professor, Department of Veterinary and Animal Science
Professor of Medicine, Tufts School of Medicine
Adjunct Professor, Department of Biology, UMass Amherst
Email: schneyer [at] cns [dot] umass [dot] edu
Office location: PVLSI
3601 Main Street
Springfield, MA 01199
BS University of Pennsylvania, 1976
MS University of Miami, 1980
Ph.D. University of Miami, 1983
Albany Medical College, 1984-1986
ANIMLSCI 697J - Genes, Cells and Development
Members of the TGFβ family are critical regulators of cell growth, survival and function and have important roles in development and tissue fate determination. Their roles in homeostatic regulation of tissues and systems in adults is becoming increasingly appreciated. My lab focuses on the activin/myostatin/GDF11 branch of the TGF 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, -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, in contrast to global FST KO mice, but are subfertile, and also have metabolic phenotypes, but in most cases these are distinct from those of the FSTL3 KO mice. 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 -cell expansion since the FSTL3 KO mouse had larger islets with more b-cells than WT mice. Our current research explores the source of these new -cells with the hope that understanding regulation of -cell expansion in these mice could lead to new treatments for diabetes in which -cells fail to produce sufficient insulin to control blood glucose.
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 TGF 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.
|Scholl , William MCB Graduate Student||wscholl [at] umass [dot] edu||PVLSI|