ZeRuth Lab Research

Research Overview

Our lab is broadly interested in understanding how transcription factor networks control development and characterizing how mutations in transcription factors give rise to disease.  We are currently investigating transcription factor networks that mediate the development of the pancreas and kidney and their proper function in the mature organism.  Using the zebrafish as a model organism, we hope to 1) understand how endocrine and ductal lineages are specified in the pancreas, 2) to characterize the signals that regulate β cell mass both neonatally and in response to nutrient excess, and 3) to delineate the molecular events that result in β cell dysfunction preceding type 2 diabetes.  We are also exploring 4) how changes in the expression of key developmental pathways result in the formation of renal cysts and contribute to the development of polycystic kidney disease (PKD).  Finally, we are using zebrafish, tissue culture, and in vitro techniques to 5) determine the role a tiny, hair-like organelle called the primary cilium plays in pancreatic and renal development.  We hope this research will lead to the identification of therapeutic targets for the treatment of diabetes and other metabolic diseases and ultimately allow for the generation of tissues that can be used for transplantation therapy. 

The Zebrafish (Danio rerio) as a model organism

The zebrafish (Danio rerio) has emerged as a powerful model for the study of pancreas development for several reasons including short generation time, rapid development, and amenability to genetic techniques. Indeed, a single female can give rise to 200-300 eggs at a time and the transparent embryos develop externally allowing for efficient visualization of developmental processes. Importantly, the zebrafish pancreas is similar to the mammalian pancreas both morphologically and functionally and the developmental programs that promote pancreatic development appear to be highly evolutionarily conserved. The zebrafish additionally has several unique features lacking in rodent models such as compartmentalized endocrine cell formation in the dorsal bud that allows for discerning factors required for endocrine versus exocrine differentiation and the ability to regenerate β-cells following destruction. These factors in combination with its ability to be used in high-throughput genetic and small molecule screens make the zebrafish a powerful model for the study of pancreas development and diabetes.

The Pancreas

The vertebrate pancreas is comprised of three major cell types: acini, ductal, and endocrine.  The role of the acinar cells is to secrete digestive enzymes which are then carried by the ducts into the duodenum.  The endocrine cells make up a very small proportion of the pancreas (5-10%) and are arranged in clusters called islets of Langerhans.  The major role of the pancreatic islets is to maintain glucose homeostasis by secreting hormones directly into the bloodstream through neighboring capillaries

The endocrine pancreas is made up of 5 major cell types.  Beta cells are the most numerous endocrine cells and are typically located toward the center of the islet and surrounded by the other cell types.  Insulin is released from beta cells in response to high blood glucose levels to signal the uptake of glucose by peripheral tissues such as muscle and fat to be used as energy.  Conversely, during periods of low blood glucose, glucagon is secreted by the alpha cells to signal the breakdown of glucose stored in the liver so that it can be used as energy.  The remaining three endocrine cell types help fine tune the regulation of insulin and glucagon.

Following the specification and development of the pancreas, the islet mass must be regulated in order to meet the demands of the organism.  Our lab is interested in identifying and characterizing transcription factors involved in the specification of endocrine cells in the pancreas during development and their subsequent maturation and expansion.