Cellular and molecular regulation of renal progenitor populations : the roles of receptor tyrosine kinase signaling in nephron and collecting duct progenitor maintenance and differentiation

Disruptions in MAPK/ERK signaling have been implicated in the development of various renal diseases including renal cancer, nephrotic syndrome, and Wilms’ tumor. Our lab has shown that MAPK/ERK is a crucial regulator of normal kidney development, where its functions are required both for ureteric bud branching morphogenesis as well as for nephrogenesis and progenitor expansion. Thus, understanding the role of MAPK/ERK signaling in kidney development is crucial for advancing our understanding of the mechanisms underlying renal diseases and for the development of new therapeutic strategies. Kidney development begins when signals originating from the metanephric mesenchyme, including GDNF, induce the initial ureteric bud outgrowth from the Wolffian duct and drive subsequent branching morphogenesis. The ureteric bud is comprised of the collecting duct progenitors, and their maintenance depends on the metanephric mesenchyme-derived signals. In turn, signals from the ureteric bud induce the metanephric mesenchyme, comprised of the nephron progenitor cells, to differentiate and begin the process of nephron formation. Due to the reciprocal interactions, the extent of ureteric bud branching dictates not only the size and shape of the organ but also the final nephron number. Nephron number additionally depends on the molecular regulation and maintenance of the nephron progenitors. As the kidney is a non-regenerating organ, nephron endowment is ultimately defined during the fetal period, and low nephron number predisposes renal and related cardiovascular issues throughout life. This thesis work found that MAPK/ERK maintains ureteric bud cells as undifferentiated and regulates renal progenitor cell maintenance through effects on chromatin accessibility and energy metabolism. MAPK/ERK-dependent nephron progenitor metabolism functionally contributes to progenitor preservation by controlling pyruvate availability and proline metabolism in developing kidneys. Furthermore, my data shows that monitoring the degree of signaling activity is a crucial way by which GDNF and possibly other molecules contribute to the specification of the lifespan of nephron progenitors. These studies provide some previously missing information about the regulation of renal development, which could contribute to the improvement of diagnostic and/or therapeutic strategies for renal diseases.