Shroom3 in nephron formation

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The long-term focus of my research program is to define the fundamental mechanisms of kidney development. Kidneys are composed of millions of nephrons that filter the blood and reabsorb ions, proteins, and water. This makes the nephron essential for homeostasis in virtually every multicellular organism. The proper development of the nephron is a fundamental requirement for proper nephron function. Nephron formation begins when loosely packed nephron progenitor mesenchyme (NPM) cells tightly cluster, alter their morphology, and transition to epithelia. Through extensive morphogenesis these structures progress through various stages to form the nephron. The correct clustering, organizing, and morphogenesis of the NPM cells is essential for setting the proper foundation for nephron function, yet little is known about the mechanisms regulating these processes. Shroom3 is an actin binding protein that regulates cell morphogenesis in developing epithelial such as the gut, eye, and neural tube. Despite the importance of cell morphogenesis for kidney development and significant evidence that Shroom3 is associated with poor kidney function, the fundamental mechanisms of Shroom3's actions in the kidney is lacking. Our published data demonstrates that adult Shroom3 mutant mice have poorly functioning nephrons composed of disorganized epithelia. Our unpublished data demonstrates that Shroom3 is 1) expressed in the NPM, 2) is required for NPM organization, 3) is required for clustering and renal vesicle formation. This data provides us with the opportunity to generate novel insights into the cellular morphogenetic mechanisms required for NPM cell clustering and patterning of the nephron. Using our newly generated Shroom3 conditional mouse model we will build on our exciting findings and dissect the cellular mechanisms by which Shroom3 regulates NPM aggregation and nephron formation. In this proposal we will contribute to our long-term goal by performing objective 1: Determine the effects of Shroom3 on the NPM cell morphology and the NPM transcriptome 2) Define the mechanisms by which shroom3 modulates nephron progenitor morphology and defining the Shroom3 protein interactome. The proposed plan will determine the contribution of Shroom3 in the regulation of nephron progenitor cell morphology, identify how morphological changes affect cellular communication, and identify up and down stream modulators of Shroom3. These studies will also extend our understanding of nephron progenitor formation and patterning during kidney development. Further, these studies will extend our understanding of Shroom3 mechanisms in cell and tissue morphogenesis and will contribute significant knowledge for future research. In addition, these studies will also provide further understanding as to why Shroom3 is associated with poor kidney function and address questions as to the most common cause of childhood kidney failure, which is abnormal kidney development.