Role of Etv4 and Etv5 in the self-renewal and differentiation of nephron progenitors

Abstract: Etv4 and Etv5 (Etv4/5) are two transcription factors expressed in the developing mouse kidney, specifically in the ureteric bud tips, the metanephric mesenchyme and the renal vesicle. Our preliminary data using a mouse model of Etv4/5 deletion in the nephron progenitor cells (NPCs) and their progeny demonstrate a critical role for these transcription factors during nephrogenesis; absence of Etv4/5 cause premature NPC exhaustion, thinning nephrogenic zone and hypoplastic/cystic kidneys at birth. In addition, these mutants present segmentation defects as early as the s-shape body stage. We have generated RNAseq data from NPC mutant and littermate control embryonic kidneys and identified Wnt4 as a downstream target of Etv4/5. Based on these preliminary data we hypothesize that Etv4/5 modulate nephrogenesis, at least in part, by downregulating Wnt signaling in the NPCs and in the developing nephron. We further hypothesize that this downregulation is required to favor both self-renewal of NPCs and differentiation of the early nephron. We will test these hypotheses in two aims. In aim one we will investigate the crosstalk between Fgfs, Etv4/5 and Wnt4 signaling to promote self-renewal/prevent differentiation of the NPCs. In aim two we will investigate how Etv4/5 and Wnt4 signaling affect nephron differentiation. These studies will provide further insight into the signaling network driving progenitor self-renewal and differentiation; they will also expand our knowledge of the cellular readout of Etv4 and Etv5 expression, therefore having a significant impact not only on the field of developmental biology but also in cancer and in vitro organogenesis.