A vital part of understanding the pathology of organ systems in the human body is to determine the developmental mechanisms responsible for their induction, patterning, growth and differentiation. Alterations in any one of these processes can lead to debilitating or life- threatening diseases. One example is polycystic kidney disease (PKD) which accounts for 8 percent of all cases of end state renal kidney disease. PKD is thought to result from a failure in differentiation of nephronic epithelia, underscoring the need to study mechanisms operating in embryonic life to understand adult disease. The long term goal is elucidation of how the nephron, the excretory unit of the kidney, is formed. The studies focus on the roles of two families of signals, Wnts and Hedgehogs whose role is patterning the early embryo of diverse animal species is well substantiated. The hypothesis is that these same signals are recruited later in development to regulate organ development. To test this hypothesis, the Principal Investigator has chosen the kidney as a model. The choice reflects the rich embryological history associated with this organ, the excellent culture systems available to study interactions and the relevance to human disease. Nephron formation requires inductive signaling between a branching tubular epithelial network, the ureteric bud, and adjacent mesenchymal cells. The ureteric bud induces formation of simple, epithelial tubules. These, then undergo a complex morphogenesis, fusing with the ureteric bud-derived collecting duct system, to generate the tubular network of the nephron. Wnt-4 is a mesenchymal signal required for tubule induction. The Principal Investigator will use culture of kidney rudiments and analysis of mouse mutants to determine whether Wnt-4's action is antagonized by a binding partner, sFRP2. Growth of the ureteric epithelium is dependent on cRET activation at the tips. The Principal Investigator will use genetic approaches to investigate the potential role of two Wnts, Wnt-11 and Wnt-6, in this process. Further, the Principal Investigator will use transgenic mice to investigate whether local activation of cRET is required for branching. To determine whether microtubule based processes are involved in branching they will generate transgenic strains to visualize microtubules in the ureteric bud. More distal regions of the ureteric epithelium do not branch, and express distinct signals, Wnt-7b and Shh. Their roles in this region of the kidney will be determined by genetically modifying their expression. These approaches will include the development of new transgenic mouse strains which will allow both tissue and temporal regulation of gene expression in the ureteric bud and its derivatives. Finally, given the importance of Wnt-signals, they will start to examine their receptors in the kidney.
Showing the most recent 10 out of 36 publications
