Expansion of the renal capsular stroma, ureteric bud branching defects and cryptorchidism in mice with Wilms tumor 1 gene deletion in the stromal compartment of the developing kidney.

Development of the mammalian kidney is orchestrated by reciprocal interactions of stromal and nephrogenic mesenchymal cells with the ureteric bud epithelium. Previous work showed that the transcription factor Wilms tumor 1 (WT1) acts in the nephrogenic lineage to maintain precursor cells, to drive the epithelial transition of aggregating precursors into a renal vesicle and to specify and maintain the podocyte fate. However, WT1 is expressed not only in the nephrogenic lineage but also transiently in stromal progenitors in the renal cortex. Here we report that specific deletion ofWt1in the stromal lineage using theFoxd1(cre)driver line results at birth in cryptorchidism and hypoplastic kidneys that harbour fewer and enlarged ureteric bud tips and display an expansion of capsular stroma into the cortical region.In vivoandex vivoanalysis at earlier stages revealed that stromal loss ofWt1reduces stromal proliferation, and delays and alters branching morphogenesis, resulting in a variant architecture of the collecting duct tree with an increase of single at the expense of bifurcated ureteric bud tips. Molecular analysis identified a transient reduction ofAldh1a2expression and of retinoic acid signalling activity in stromal progenitors, and ofRetin ureteric bud tips. Administration of retinoic acid partly rescued the branching defects of mutant kidneys in culture. We propose that WT1 maintains retinoic acid signalling in the cortical stroma, which, in turn, assures proper levels and dynamics ofRetexpression in the ureteric bud tips, and thus normal ramification of the ureteric tree. (c) 2020 The Authors.The Journal of Pathologypublished by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.