Wnt9b Signals Through Two Distinct Pathways to Regulate Progenitor Maintenance, Differentiation and Morphogenesis During Kidney Development

The development of the kidney is dependent upon reciprocal interactions between the ureteric bud epithelium and a mesenchymal progenitor population known as the metanephric mesenchyme. Signals from the ureteric bud cause a subset of the progenitors to differentiate into tubules while the remainder of the mesenchyme undergoes proliferation/self renewal. This process of progenitor expansion and differentiation reiterates itself during the course of development, ultimately resulting in the formation of approximately 20,000 tubules per mouse kidney. Establishment of the correct number of tubules depends on a careful balance between the induction of new tubules and the expansion of the existing tubule progenitor cells. The molecular mechanisms by which this balance is achieved are poorly understood. Previous studies suggested that Wnt/-catenin signaling was necessary and sufficient to induce tubule formation. Further, it was hypothesized that the pathway must be repressed in the progenitors to keep them in an undifferentiated state. However, using a combination of microarray analysis and genetics, I have found that Wnt/-catenin signaling is active in the progenitor compartments. My data indicate that rather than inhibiting _-catenin activity, factors in the progenitor cells (primarily the transcription factor Six2) alter the transcriptional output of -catenin signaling. Wnt/-catenin signaling is required for stem cell renewal/proliferation of the progenitor cells. These data reveal a mechanism through which cells receiving the same Wnt9b signal can respond in distinct ways (differentiation vs. proliferation). Utilizing this simple mechanism, the kidney balances the induction of new tubules and the maintenance of tubule progenitors, thereby insuring formation of the proper number of tubules. While the mechanisms regulating tubule formation have been well studied, little is known of the mechanisms that establish the length or diameter of these tubules. In the kidney, defects in the establishment or maintenance of tubule diameter are associated with one of the most common inherited human disorders, polycystic kidney disease. Here, I show that attenuation of Wnt9b signaling during kidney morphogenesis affects the planar cell polarity of the epithelium and leads to tubules with significantly increased diameter. Although previous studies showed that polarized cell divisions played an important role in the maintenance of postnatal kidney tubule diameter, we find that during early embryonic development, cell divisions are randomly oriented. Therefore the orientation of cell division plays little role in kidney tubule diameter establishment. Instead, our data suggest that diameter is established during early morphogenetic stages by convergent extension processes and maintained by polarized cell divisions. Wnt9b, signaling through the non-canonical Rho/Jnk branch of the Wnt pathway, is necessary for both of these processes. These findings provide novel insights into the molecular mechanisms that regulate the kidney tubule development and morphogenesis and greatly enhance our ability to generate kidney stem cells and engineer tubules for damaged organs.