Growth/Differentiation Factors in Organogenesis and Their Roles in Tumorigenesis

Morphogenesis in the differentiating metanephros is regulated by reciprocal interactions between ureteric bud (UB) epithelia and the metanephric mesenchyme (MM). The UB invades the overlying MM and induces conversion of the mesenchyme into stromal and epithelial elements, which form the nephron. In turn, the MM stimulates the UB to grow and branch, forming the collecting duct system. The Differentiation and Neoplasia Section focused on the elucidation of mechanisms of inductive signaling in metanephric development, seeking (1) the ligands responsible for renal progenitor survival and nephronic differentiation, (2) other non-inductive regulatory factors of nephrogenesis, (3) the molecular targets of induction, (4) dysregulation of normal inductive signaling during development of pediatric neoplasms such as the Wilms tumor or congenital mesoblastic nephroma, and (5) targeting the dysregulated signaling in these tumors. The Section used both explants of metanephric rudiments and mouse genetic models in these studies. We also had efforts to map the genetic locus responsible for sensitivity to nephroblastoma (Wilms) induction in rats. We expected that as we deciphered the roles of various inductive signaling mechanisms in development and understood their dysregulation in tumorigenesis, our studies would lead to novel animal models and targeting agents for drug development.