Kidney development involves reciprocal signalling between metanephric mesenchyme (which differentiates into the nephrons, the kidney's functional units), ureteric bud (UB) epithelium (which undergoes branching morphogenesis to form the urinary collecting ducts) and stromal mesenchyme (which differentiates into the renal interstitium). In this issue, two papers provide new information about how kidney development is regulated in mice.
On p. , Cathy Mendelsohn and colleagues describe a novel stromal-UB retinoic acid (RA) signalling pathway that is crucial for collecting duct formation. The receptor protein kinase Ret is expressed in the UB and is required for both bud formation and branching. Ret expression in the UB is controlled by RA receptors (RARs), widely expressed RA-activated transcription factors, but as RA is made in both UB and stromal cells, it has been unclear whether RA regulates Ret in an autocrine or paracrine fashion. Now, by expressing a dominant-negative RAR in mouse UB cells, the researchers show that UB RARs, rather than stromal cell RARs, are required for Ret transcription; other experiments indicate that RA from stromal, rather than from UB, cells activates UB RARs. This paracrine RA signalling pathway is probably conserved, suggest the researchers, and might be used elsewhere during development.
On p. , Silvia Cereghini and colleagues report that the homeodomain transcription factor vHNF1 is a key regulator of ureteric branching and early nephrogenesis. Heterozygous mutations or deletions in the gene encoding HNF1 cause ‘Renal Cysts and Diabetes’, a human syndrome that includes multiple kidney and genital tract abnormalities. Because vHnf1 inactivation in mice causes early embryonic lethality, the researchers analysed tetraploid and diploid chimeras to investigate its role during early kidney development. Their experiments indicate that vHNF1 regulates several stages in renal development, including the timed outgrowth of the UB and its subsequent branching, nephric duct epithelial maintenance and early nephrogenesis. They also report that vHNF1 acts directly upstream of Wnt9b during the mesenchymal–epithelial transitions that underlie the initiation of nephrogenesis. Thus, they conclude, vHNF1 is a crucial component of the regulatory circuits that controls early urogenital development.
Together, these two papers shed new light on the complex signals and regulatory circuits involved in renal development.
