PAX-2 IS REQUIRED FOR MESENCHYME-TO-EPITHELIUM CONVERSION DURING KIDNEY DEVELOPMENT

The conversion of mesenchyme to epithelium during the embryonic develo pment of the mammalian kidney requires reciprocal inductive interactio ns between the ureter and the responding metanephric mesenchyme. The P ax-2 gene is activated in the mesenchyme in response to induction and is subsequently downregulated in more differentiated cells derived fro m the mesenchyme. Pax-2 belongs to a family of genes, at least three o f which encode morphogenetic regulatory transcription factors. In orde r to determine the role of Pax-2 during kidney development, we have ge nerated a loss-of-function phenotype using antisense oligonucleotides in mouse kidney organ cultures. These oligonucleotides can specificall y inhibit Pax-2 protein accumulation in kidney mesenchyme cells, where the intracellular concentrations are maximal. The kidney organ cultur es were stained with uvomurulin and laminin antibodies as markers for epithelium formation. With significantly reduced Pax-2 protein levels, kidney mesenchyme cells fail to aggregate and do not undergo the sequ ential morphological changes characteristic of epithelial cell formati on. The data demonstrate that Pax-2 function is required for the earli est phase of mesenchyme-to-epithelium conversion.