Molecular function of Tbx18 in ureter development

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Formation of the ureter relies on a multi-step developmental program that is characterized by the in-teraction of different mesenchymal and epithelial cell lineages of the early metanephric field. Recent findings have revealed the importance of the ureteric mesenchyme and the T-box transcription factor Tbx18 therein for this process. In Tbx18-/- mice, the ureteric mesenchyme disperses and remains undifferentiated leading to hydroureter formation by functional obstruction. Here, we want to define the molecular pathways that confer the spatial restriction of Tbx18 expression in the early metanephric field and characterize by genetic loss- and gain-of-function approaches the genetic circuits that act downstream of Tbx18 to mediate its function in the ureteric mesenchyme. The functional significance of ephrin-signaling and Sox9 transcriptional activity in compartmentalization and aggregation of urete-ric mesenchyme shall be studied. Micro-array analysis of Tbx18-/- ureters shall identify additional mediators of Tbx18 function but also of Bmp- and Shh-signaling in this tissue. We expect from these experiments new insight into the genetic control of early ureter development and into the etiology of congenital malformation of the urinary tract.