Peter Wiebe's Research
TRANSCRIPTIONAL REGULATION OF PDX1 BY PTF1A DURING PANCREAS DEVELOPMENT
Pdx1 (pancreas and duodenum homeobox 1) and Ptf1a (pancreastranscription factor 1a) are both transcription factors that are expressed early and broadly in the pancreas as it begins to develop. Each of these factors are also critical for pancreas development, as deletion of either of these genes results in pancreatic agenesis. Early in development, both Pdx1 and Ptf1a are expressed throughout the pancreatic epithelium. However, Pdx1 expression later becomes enriched in the insulin-producing beta cells, while Ptf1a expression becomes enriched in the acinar tissue of the pancreas. How these dynamic expression patterns are regulated has not yet been fully elucidated, but understanding how expression of these critical factors is regulated is key to understanding how the pancreas normally develops, and may provide ways to manipulate this process to better treat diabetes. Using a cell lineage tracing technique, we identified a region of the Pdx1 promoter that is necessary for the early/broad expression of Pdx1 as well as regions necessary for the later beta cell-enriched expression of Pdx1. Within the former region (termed Area III), I identified a binding site for the Ptf1 complex (composed of Ptf1a, HEB, and RBP). Using a transfection assay, I found that this site is required for Area III-dependent reporter gene expression, and that RBP-Jk activates expression to a greater extent than does its homologue RBP-L. Additionally, using a chromatin immunoprecipitation (ChIP) assay, we showed that Ptf1a did in fact bind in vivo to that site within the endogenous Pdx1 promoter in embryonic day 11.5 pancreatic buds. Thus, Ptf1a is an early activator of Pdx1 in the pancreas.