Notch signaling promotes nephrogenesis by downregulating Six2.

Eunah Chung,Patrick Deacon,Sierra Marable,Juhyun Shin,Joo-Seop Park

doi:10.1242/dev.143503

Eunah Chung, Patrick Deacon + Show 3 more

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https://doi.org/10.1242/dev.143503

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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 novel role of Notch in nephrogenesis. We show in mice 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 Six2 downregulation. 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 by a differentiation signal in nephrogenesis.

Highlights

In mammals, nephrons are formed only during development, with nephrogenesis stopping at 36 weeks of gestation in humans and by the fourth postnatal day in mice (Hartman et al, 2007; Hinchliffe et al, 1991; Rumballe et al, 2011)
It was believed to play a later role in nephron segmentation, with Notch required for formation of the proximal but not distal segment of the nephron (Cheng et al, 2007, 2003)
The finding that Notch is involved in the downregulation of Six2 suggests that Notch signaling has a profound impact on the gene regulatory network governing the maintenance of nephron progenitors

Summary

Introduction

Nephrons are formed only during development, with nephrogenesis stopping at 36 weeks of gestation in humans and by the fourth postnatal day in mice (Hartman et al, 2007; Hinchliffe et al, 1991; Rumballe et al, 2011). Deletion of Six disrupts the balance between self-renewal and differentiation of nephron progenitors, resulting in premature depletion of nephron progenitors accompanied by ectopic nephrogenesis (Kobayashi et al, 2008; Self et al, 2006). This illustrates the pivotal role of Six in the maintenance of progenitors and implies that downregulation of Six is a critical step for the differentiation of nephron progenitors

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