The nephron is a highly specialised unit of the kidney. It arises by mesenchymal-to-epithelium transitions. After epithelialization, a polarized renal vesicle forms, and this further differentiates into a comma-shaped body and a S-shaped body (SSB), in which the future nephron segments are mapped into proximal, intermediate and distal domains. How SSBs are patterned and subsequently differentiate during kidney morphogenesis is poorly defined. Here, two papers use complementary approaches to show that hepatocyte nuclear factor 1β (HNF1β), which is known to be required for the earliest steps of metanephric kidney development and is implicated in developmental renal pathologies, controls this early patterning.

On p. 873, Silvia Cereghini and co-workers show that conditional inactivation of Hnf1b in murine nephron progenitors causes abnormal SSB regionalisation and morphology. In particular, Hnf1b deficiency leads to the absence of a proximal-medial SSB subdomain. This defect correlates with a downregulation of Notch pathway components and of Iroquois transcription factors, and perturbs the subsequent differentiation and morphogenesis of SSBs. Using parallel studies in Xenopus embryos, the researchers show that Hnf1b is required for the acquisition of proximal and intermediate tubule fate, acting again through the Notch pathway and Iroqouis genes. Together, these results show that HNF1B is required for the acquisition of a proximal-medial segment fate in vertebrates and uncover a previously unappreciated function of a novel SSB subdomain.

Using a similar gene targeting approach, Evelyne Fischer and colleagues (p. 886) demonstrate that Hnf1b inactivation in the murine metanephric mesenchyme (MM), which gives rise to nephron progenitors, leads to drastic tubular defects. The researchers report that mutant embryos show significant alterations to SSB structure: the typical bulge of epithelial cells between the intermediate and distal SSB segments is absent in mutant embryos. The lack of Hnf1b correlates with decreased expression of several genes, including the Notch ligand Delta-like 1, and results in impaired tubular expansion and differentiation. Finally, the researchers show that the nephron defects observed in Hnf1b-deficient mice resemble those observed in human foetuses carrying HNF1B mutations. The authors conclude that HNF1β plays an essential role in controlling the formation of a specific SSB sub-compartment by activating a set of crucial kidney development genes.