The primary role of islet dysfunction in the pathogenesis of type 2 diabetes is increasingly appreciated. In particular, recent advances elucidating the genetic basis of a subset of diabetes, MODY (maturity onset diabetes of the young), have indicated links among pancreatic transcription factors, beta-cell function, pancreatic development and the diabetic phenotype. The overall goal of the proposed research is to elucidate the mechanisms whereby the homeodomain transcription factor PDX (MODY 4) controls pancreatic islet development and function. The homeodomain transcription factor PDX (also known as IPF-1, STF-1 and IDX-1) plays a critical role in early pancreatic development in mice and humans and regulates key genes in the endocrine pancreatic beta-cell, including the insulin, glucokinase and glucose transporter-2 (Glut2) genes. In the adult pancreas, PDX interacts with a members of the TALE (Three Amino acid Loop Extension) class of homeoproteins to regulate the somatostatin and elastase genes and interacts functionally with the basic-helix-loop-helix transcription factor E47 to regulate the insulin promoter. Since PDX is localized to ducts, islet beta and delta cells and, at a lower level, to exocrine acinar cells, we hypothesize that interactions of PDX with distinct nuclear partners play an important role in determining which subsets of target genes will be activated in a given cell type. The TALE class of homeodomain proteins, which include members of the Pbx, Meis, Prep and pKNOX families, are promising candidates for the modulation of lineage specific gene activation by the homeodomain protein PDX. We propose three approaches to explore this hypothesis through: A) Exploration of the role of TALE class homeoproteins in the nuclear localization of PDX, B) Identification of Pbx heterodimerization partner(s) on the tissue-specific somatostatin promoter upstream enhancer (SMS- UE), and C) Characterization of novel rat islet Pbx family members.
