Sall1 co-operates with Six2 to actively maintain nephron progenitors

The balanced self-renewal and differentiation of nephron progenitors is critical for kidney development. While a nuclear factor Sall1 is essential for kidney formation, its role in the nephron progenitors remains unknown. We here report that Sall1 deletion in the Six2-positive nephron progenitors and their derivatives results in severe progenitor depletion and apoptosis of the differentiating nephrons. Microarray analysis of the inducible Sall1 deletion reveals that Sall1 activates genes in the progenitors while represses genes in the differentiating nephrons. Many progenitor-related gene loci are co-occupied by Sall1 and Six2, and Sall1 binds to Six2. In contrast, Sall1 does not bind to the Wnt4 or FGF8 loci that are major targets suppressed by Six2. Sall1-mediated repression is also independent of its binding to DNA. Thus Sall1 co-operates with Six2 as an activator in the nephron progenitors, while functions as a repressor in the Six2-negative differentiating nephrons, thereby maintaining these populations.