Diversity Supplement: Novel Role of Nephron Epithelialization in Nuclear Signaling

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PROJECT SUMMARY/ ABSTRACT OF PARENT GRANT (2R01DK115655-04A1): NOVEL ROLE OF NEPHRON EPITHELIALIZATION IN NUCLEAR SIGNALING **R01 Project Summary/Abstract has been revised so that they are feasible, given that our grant budget was subjected to a global NIDDK reduction of 30% (the 5th year of the budget period was eliminated in addition to a 12% cut from each of years 1-4). Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of pediatric end- stage renal disease resulting in the need for kidney transplant. They occur in almost 2% of births, making up nearly one-fourth of all birth defects. However, only 14% of cases have a known genetic cause. Many CAKUT cases result from defects in the formation of nephrons, which are composed of epithelial tubules that are required for the proper function of the kidney. Prior studies indicate that disruption of either the planar cell polarity (PCP) pathway or exocyst vesicle complex result in malformation of the nephric tubules, indicating that these components are required for proper tubule formation. In our previous studies, we evaluated how tubulogenesis is facilitated through the PCP and exocyst complexes independently. We investigated distinct models by which Daam1, a formin protein that assembles actin filaments as part of the Wnt/planar cell polarity pathway, and Dnmbp/Tuba, which regulates exocytic vesicle targeting, facilitate tubulogenesis by promoting the generation of cell-cell contacts between nephron progenitor cells. We discovered a novel mechanism that utilizes the Wnt/PCP formin protein Daam1 to drive cell junction formation between nephron progenitor cells to generate tubules by polymerizing actin to stabilize cadherin at adherens junctions. Additionally, our results indicate that the exocyst- associated component Dnmbp facilitates the targeting of junctional components to initiate formation of these cell contacts between nephron progenitors. Despite this progress, we do not understand how the formation of cell- cell contacts influences the developmental processes of tubule epithelialization and morphogenesis in developing nephrons. To address this significant question, we will build upon on our important discoveries to evaluate how cell junction formation impacts the development of the nephric tubules by: 1) Identifying how the interaction between Daam1 and Dnmbp regulates cell-cell contact formation between nephron progenitors and 2) Determining whether Daam1's role in junction formation regulates beta-catenin's junctional versus Wnt signaling roles during nephrogenesis. Overall, the experiments proposed in this application will facilitate a new understanding of how cells interact and communicate to carry out tubulogenesis that has relevance in multiple organ systems. The quantitative evaluation of cell biological mechanisms involved in nephric development is a new area of study that will contribute valuable insights into epithelialization and morphogenesis mechanisms underlying tubulogenic processes.