Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2.

Abstract

Metanephric mesenchyme gives rise to both the epithelial cells of the nephron and the stromal cells of the mature kidney. The function of the stroma. in kidney morphogenesis is poorly understood. We have generated mice with a null mutation in the Winged Helix (WH) transcription factor BF-2 to examine its function during development. BF-2 expression within the developing kidney is restricted to the stromal cell lineage. Homozygotes die within the first 24 hr after birth with abnormal kidneys. Mutant kidneys are small, fused longitudinally, and rotated 90 degrees ventrally. Histological examination reveals a smaller collecting system, numerous large condensations of mesenchyme, and a decrease in the number of nephrons. Using molecular markers we show that induction and condensation of the nephrogenic mesenchyme occurs normally in mutant. The disruption of BF-2 reduces the rate of differentiation of the condensed mesenchyme into tubular epithelium, as well as the rate of growth and branching of the ureter and collecting system. Our findings demonstrate that BF-2 and stromal cells have essential functions during kidney morphogenesis. Furthermore, they suggest that BF-2 controls the production, by the stroma, of signals or factors that are required for the normal transition of induced mesenchyme into tubular epithelium and full growth and branching of the collecting system.

GDNF/Ret signaling and the development of the kidney

“…(5)(6)(7)(8) It has long been believed that the MM controls many aspects of UB growth and branching through inductive interactions and, more recently, it has been learned that the renal stroma, which is derived from a distinct cell population in the metanephric blastema, is also important for normal UB development. (9)(10)(11)(12) A number of growth factors expressed by the MM and/or stromal cells or the UB itself, including members of the FGF, TGF-b and Wnt families, have been implicated in the control of UB branching morphogenesis. Other cell surface and extracellular matrix proteins such as integrins, heparan sulfate proteoglycans and matrix metalloproteases also appear to play roles in branching morphogenesis in the kidney as well as in other organs.…”

The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation.

“…Interestingly, a null mutation in BF 1 led to a decrease in the size of the cerebral hemispheres through a reduction in cellular proliferation, indicating BF1 as a positive regulator of proliferation (Xuan et al 1995). The related winged helix protein BF2 was shown to have an essential role in kidney morphogenesis, as mice with a null mutation for this gene exhibit a reduced rate of growth and branching of the ureter and collecting duct system (Hatini et al 1996). In addition, the oncogene in alveolar rhabdomyosarcoma is a fusion protein between the paired box transcription factor Pax3 and another winged helix gene, termed FKHR (Galili et al 1993).…”

Early nephron formation in the developing mouse kidney

“…One possibility is that a local signal from the epithelium is attenuated as it induces adjacent MM cells and so limits the number of cells that can join the aggregate, but there are other mechanisms that might work here ; it will be interesting to study this process in the BF-2 k\k mouse, in which abnormally large nephrogenic aggregates form (Hatini et al 1996). The mechanism by which epithelialisation takes place is also unclear and there are two obvious possibilities.…”

“…It is also expressed in MM and is initially localised to the cap of cells surrounding the tip of the ureteric bud within the central part of the kidney (e.g. Hatini et al 1996), and is thus coexpressed with NCAM. From about E13 onwards, however, the Pax2j MM cells are located at the kidney periphery as nephron-forming blastemal cells.…”