DepartmentKidney Development
Publication date30-Apr-2014

Shoichiro Kanda, Shunsuke Tanigawa, Tomoko Ohmori, Atsuhiro Taguchi, Kuniko Kudo, Yutaka Suzuki, Yuki Sato, Shinjiro Hino, Maike Sander, Alan O. Perantoni, Sumio Sugano, Mitsuyoshi Nakao, and Ryuichi Nishinakamura (2014) Sall1 maintains nephron progenitors and nascent nephrons by acting as both an activator and a repressor. J. Am. Soc. Nephrol. Epub ahead of print

The balanced self-renewal and differentiation of nephron progenitors are critical for kidney development and controlled, in part, by the transcription factor Six2, which antagonizes canonical Wnt signaling-mediated differentiation. A nuclear factor, Sall1, is expressed in Six2-positive progenitors as well as differentiating nascent nephrons, and it is essential for kidney formation. However, the molecular functions and targets of Sall1, especially the functions and targets in the nephron progenitors, remain unknown. Here, we report that Sall1 deletion in Six2-positive nephron progenitors results in severe progenitor depletion and apoptosis of the differentiating nephrons in mice. Analysis of mice with an inducible Sall1 deletion revealed that Sall1 activates genes expressed in progenitors while repressing genes expressed in differentiating nephrons. Sall1 and Six2 co-occupied many progenitor-related gene loci, and Sall1 bound to Six2 biochemically. In contrast, Sall1 did not bind to the Wnt4 locus suppressed by Six2. Sall1-mediated repression was also independent of its binding to DNA. Thus, Sall1maintains nephron progenitors and their derivatives by a unique mechanism, which partly overlaps but is distinct from that of Six2: Sall1 activates progenitor-related genes in Six2-positive nephron progenitors and represses gene expression in Six2-negative differentiating nascent nephrons.



Figure 1
Sall1 deletion in nephron progenitors results in hypoplastic kidney (panel B), and progenitor depletion (red cells shown by the arrowhead in panel D).
ad : adrenal gland, kid : kidney, bl : bladder, ov : ovary, te : testis



Figure 2

In nephron progenitors, Sall1 cooperates with Six2 and activate key genes for kidney development, including Osr1, Robo2, and Eya1. In contrast, Sall1 binds to the Mi2/NuRD complex and represses genes expressed in differentiating nascent nephrons, such as Nkx6.1.