Molecular function of Wnt/ß-Catenin signaling in the development of the ureteric mesenchyme in the mouse

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Structural basis of the contractile activity of the ureter is an outer mesenchymal investment of smooth muscle cells and fibroelastic material that arises through a multi-step cellular program from an undifferentiated pool of mesenchymal precursor cells. Although congenital anomalies of the ureteric wall are frequent and may have deleterious consequences for renal function, little is known about the molecular circuits that orchestrate the development of the ureteric mesenchyme. In the first funding period we have shown that Wnt signals from the ureteric epithelium act via the canonical Ctnnb1-dependent pathway to regulate mesenchymal proliferation and differentiation. Here, we want to gain deeper insight into the molecular function of Wnt signaling in ureter development in the mouse by using a combination of tissue specific gene targeting studies in vivo, pharmacological activation and inhibition in explant cultures, and large scale molecular assays. Specifically, we wish to characterize the possible interaction of Wnt signaling with Shh and Bmp4 signaling in mesenchymal proliferation and differentiation, and identify and characterize Wnt-dependent transcription factor activities that mediate specific cellular programs in the ureteric mesenchyme. Here, one focus will be analysis of the T-box transcription factor genes Tbx2 and Tbx3. We expect from these studies new insights in the molecular mechanisms that control smooth muscle cell differentiation of visceral organs, and into the etiology of congenital obstructive nephropathy.