Pea3 and Erm Function during Ureteric Bud Branching Morphogenesis

Columbia University Health Sciences, New York NY

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Tissues of epithelial origin, such as the kidney, arise through the branching, and subsequent morphogenesis, of a pre-existing structure, the ureteric bud (UB). In the kidney, GDNF signals through the Ret receptor and directs the branching of the UB. Improper expression of either GDNF or Ret is the cause of nearly 60% of human renal aplasia. Furthermore, GDNF was found to regulate the expression of two transcription factors, Pea3 and Erm. Both Pea3 and Erm have been identified as critical for proper UB branching morphogenesis, yet the specific requirement for and mechanism of action are still unknown. The overall goal of this study is to understand how Pea3 and Erm contribute to, and direct the development of the UB. Two distinct yet intertwined approaches are proposed to study function of Pea3 and Erm during kidney development. A cell biological approach will rely on the generation of mosaic kidneys to determine how Pea3 and Erm contribute to and influence the developing UB. We further propose to misexpress Erm in the UB to elucidate the function of Erm during UB morphogenesis. A second and more biochemical approach will use Pea3 and Erm null animals to identify genes that are regulated by Pea3 and Erm using microarray analysis. This analysis will identify genes that are regulated by Pea3 and Erm and therefore may be important for UB branching morphogenesis. In identifying genes that are regulated by Pea3 and Erm during kidney development, it is possible to identify novel targets for treatments of kidney related illnesses. Many birth defects such as renal aplasia or hypoplasia, as well as postnatal diseases including, diabetes, hypertension and polycystic kidney disease, affect either the growth or development of the kidney. A better understanding of the mechanisms of kidney development, could lead to new therapies to treat these and other kidney diseases. [unreadable] [unreadable] [unreadable]