MICE LACKING THE HOMEODOMAIN TRANSCRIPTION FACTOR NKX2.2 HAVE DIABETES DUE TO ARRESTED DIFFERENTIATION OF PANCREATIC BETA-CELLS

The endocrine pancreas is organized into clusters of cells called isle ts of Langerhans comprising four well-defined cell types: alpha, beta, delta and PP cells. While recent genetic studies indicate that islet development depends on the function of an integrated network of transc ription factors, the specific roles of these factors in early cell-typ e specification and differentiation remain elusive. Nkx2.2 is member o f the mammalian NK2 homeobox transcription factor family that is expre ssed in the ventral CNS and the pancreas. Within the pancreas, we demo nstrate that Nkx2.2 is expressed in alpha, beta and PP cells, but not in delta cells, In addition, we show that mice homozygous for a null m utation of Nkx2.2 develop severe hyperglycemia and die shortly after b irth. Immunohistochemical analysis reveals that the mutant embryos lac k insulin-producing beta cells and have fewer glucagon-producing a cel ls and PP cells. Remarkably, in the mutants there remains a large popu lation of islet cells that do not produce any of the four endocrine ho rmones. These cells express some beta cell markers, such as islet amyl oid polypeptide and Pdx1, but lack other definitive beta cell markers including glucose transporter 2 and Nkx6.1. We propose that Nkx2,2 is required for the final differentiation of pancreatic beta cells, and i n its absence, beta cells are trapped in an incompletely differentiate d state.