The signaling pathways controlling Ureteric Bud (UB) segmentation into the renal collecting system and ureter during embryogenesis remain poorly understood despite the high incidence of human congenital defects localized to the ureter and its junction with the kidney. Our preliminary data suggest that a unique mesenchymal cell population derived from paraxial mesoderm selectively surrounds the distal UB and secretes factors such as Bone Morphogenetic Factor 4 that are required for patterning the ureter. Specifically, we propose that BMP4 controls ureter structure by activating an antagonist of receptor tyrosine kinase signaling which is known to induce branching morphogenesis. In addition, we show that Bone Morphogenetic Protein 5, another factor secreted by periureteral mesenchyme, induces UB epithelia to terminally differentiate.
The aims of this proposal will test these hypotheses describing the molecular mechanisms controlling ureter morphogenesis using established fate mapping, tissue removal, immunohistochemical, morphological, and transgenic techniques.
Aim 1) The differentiated fate of ureteral connective tissue cells derived from paraxial mesoderm will be determined and ureter morphogenesis in the absence of these cells analyzed.
Aim 2) The expression of membrane-associated Sprouty 1, an active receptor tyrosine kinase antagonist, will be correlated with sites of BMP signaling in the developing ureter. Ureter structure and the cellular distribution of Sprouty 1 will be analyzed in the developing mouse in the absence of BMP signaling.
Aim 3) Terminal urothelial cell differentiation will be analyzed in vitro and in vivo in the absence of BMP5 signaling and in the presence of ectopic BMP signaling. Results of proposed experiments will provide much needed insight into the signaling pathways mediating ureter morphogenesis, a process that is prone to abnormalities in humans.
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