Notch signaling promotes nephrogenesis by downregulating Six2

Abstract

During nephrogenesis, multipotent mesenchymal nephron progenitors develop into distinct epithelial segments. Each nephron segment has distinct cell types and physiological function. In the current model of kidney development, Notch signaling promotes the formation of proximal tubules and represses the formation of distal tubules. Here, we present a new role of Notch in nephrogenesis. We show that differentiation of nephron progenitors requires downregulation of Six2, a transcription factor required for progenitor maintenance, and that Notch signaling is necessary and sufficient for downregulation of Six2. Furthermore, we find that nephron progenitors lacking Notch signaling fail to differentiate into any nephron segments, not just proximal tubules. Our results demonstrate how cell fates of progenitors are regulated by a transcription factor governing progenitor status and a differentiation signal in nephrogenesis.