Lori Sussel, Ph.D.
Genetics and Development
1150 St Nicholas Avenue, Room 607B
New York, NY 10032
Lori Sussel, Ph.D. - Investigator Profile
Research in the Sussel lab combines molecular biology techniques and mouse embryology to study the role of regulatory factors in specifying the development and differentiation of the pancreas 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 (?), beta (?), delta (?) and PP cells. In addition, our lab has recently discovered the presence of a fifth cell type in the islet, which produces the hormone ghrelin. The ? 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 ? 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 have demonstrated that homeobox transcription factor, Nkx2.2 is essential for the specification of most glucagon-producing ? cells and all insulin-producing ? cells in the islet. We have generated an Nkx2.2 knockout mouse model that disrupts Nkx2.2 function. These mice fail to differentiate their ? cells, produce no insulin, and die of diabetes shortly after birth. Surprisingly, these mice were found to have islets filled with ghrelin-producing cells, which appear to replace the ? cell population. Studies in the lab are focused on determining the molecular mechanisms by which Nkx2.2 functions in the endocrine pancreas to regulate these early islet cell fate decisions. Recently, we have used in vivo genetic approaches to determine that Nkx2.2 functions primarily as a transcriptional repressor to specify the ? cell fate and the immature ? cell population. We are currently using several biochemical and molecular techniques to identify Nkx2.2 interacting partners and its downstream targets in the pancreas. We are also performing structure-function analysis of the Nkx2.2 gene, in vitro and in vivo.
Genetic Differentiation of Endocrine Pancreatic Cells