Lori Sussel, PhD

The research in my lab combines molecular biology techniques and mouse embryology to study the role of transcriptional regulatory factors in specifying the development and differentiation of the pancreatic islet during mouse embryogenesis. The pancreas is an essential organ required to maintain energy balance in the body; disruption of pancreatic function leads to diabetes. The endocrine pancreas is organized into clusters of cells called the islets of Langerhans, which are comprised of four well-defined hormone-producing cell types: alpha (α), beta (β), delta (δ) and PP cells. Our lab has recently discovered the presence of a fifth cell type in the islet, which produces the hormone ghrelin. The β cells represent the largest population of islet cells and produce insulin, a hormone critical for life. While all the cells of the endocrine pancreas are thought to arise from a common precursor, the early process of lineage determination and cell-type differentiation within the pancreas is unclear. To date, only a handful of regulatory factors involved in pancreas development have been identified and the molecular pathways that specify islet cell differentiation are poorly understood. For this reason, we are attempting to identify the regulatory genes that are involved in the development of pancreatic islet precursors, islet cell development and differentiation, and the propagation of β cells or their precursors. Projects in the lab are specifically focused on understanding the molecular mechanisms that determine how the pancreas initially develops in the mouse embryo and how the different islet cell populations are specified. In particular, we are exploring the following areas of research: 1. The homeobox transcription factor Nkx2.2 is essential for the formation of all insulin-producing beta cells. We are using in vitro and in vivo approaches to determine the precise molecular function of Nkx2.2 in the specification of the islet cell types. We have developed several novel mouse transgenic models to explore the function of Nkx2.2 during embryonic development. We have also generated a conditional floxed allele of Nkx2.2 to study its role in islet cell function in the adult. In addition, we are utilizing genome wide gene expression analysis combined with ChiP-Chip technology to identify the genetic networks regulated by Nkx2.2 in the islet. 2. We have identified the ghrelin-producing epsilon cell as a novel islet cell type. The function of islet ghrelin cells is unknown. We are developing immortalized cell lines and transgenic mouse models to allow us to characterize the ghrelin cell population in the islet. Preliminary studies suggest that ghrelin cells are closely related to the islet alpha and beta cell lineages and may actually be progenitors of these important islet cell types. 3. NeuroD1 is an essential basic helix-loop-helix transcription factor that has been shown to be important for islet cell development. Recent studies in the lab have demonstrated that NeuroD1 and Nkx2.2 genetically interact to regulate islet cell type specification. Studies are ongoing to determine the respective roles of the two transcription factors in this process. 4. The Gata family of zinc finger transcription factors are important in many developmental processes. We have determined that Gata4 and Gata6 have dynamic expression patterns during embryonic development and that Gata6 plays essential roles during pancreas formation and subsequent endocrine cell development. We are currently studying conditional (floxed) alleles of these genes to determine their precise functions during islet development.