Molecular function of the T-box transcription factors TBX2 and TBX3 in the development and maintenance of the epithelial lining of the urinary tract in the mouse

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The components of the upper urinary system, the kidneys and the ureters, and of the lower urinary system, the bladder and the urethra, develop from distinct epithelial and mesenchymal tissue primordia through highly integrated programs of patterning, proliferation and differentiation during embryogenesis. Despite the frequent occurrence of congenital anomalies in this organ system (CAKUT) in human newborns, we know only a fraction of the genes that regulate normal development and account for morphological anomalies when mutated, respectively. Our work in the first funding period characterized the closely related T-box transcription factors TBX2 and TBX3 as novel and essential regulators of the development of the epithelial primordia of both the murine upper and lower urinary tract: Tbx2 and Tbx3 are coexpressed in the epithelium of the nephric duct, the ureteric bud, the ureter and collecting duct system. Conditional deletion of Tbx2 or Tbx3 in these tissues is associated with partial hydroureter and megaureter, combined deletion of both genes results in a fully penetrant spectrum of CAKUT-like changes including megaureter, ureter/kidney agenesis and renal hypo/dysplasia with cystic dilations at birth. We detected a complete loss of cyto-differentiation of the epithelium of the ureter and collecting duct system, and found molecular changes indicating a premature and ectopic activation of a collecting duct program in the ureter. Tbx2 and Tbx3 are also coexpressed in the epithelium of the developing and mature bladder, and are required therein for stratification and urothelial differentiation.In a second funding period we want to decipher the molecular function and regulation of TBX2/TBX3 in the epithelial lining of the upper and lower urinary tract both in development and homeostasis using a combination of tissue-specific gene targeting and misexpression studies in vivo, and small and large-scale transcriptomic and proteomic assays. Specifically, we wish to- define the molecular changes associated with loss and gain of Tbx2/Tbx3 function in these tissues and developmental contexts- identify the direct targets of their transcriptional activity and characterize the functional contribution of these genes to the observed phenotypic changes- characterize the regulatory module in which the two factors act and- identify and characterize protein interaction partners important for the transcriptional repression activity of TBX2 and TBX3. We expect from these experiments new insight into the molecular control of upper and lower urinary tract urothelial development and homeostasis, into the molecular function of two important transcriptional regulators, and into the etiology of congenital anomalies of the urinary tract observed in human patients.