ZINC FINGERS IN KIDNEY DEVELOPMENT

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Metanephric blastema differentiates into kidney following conversion of the nephrogenic cord by migrating ureteric bud epithelium. While various morphologic events in this process have been studied observationally, the molecular and biochemical basis for the prestructural conversion of renal mesenchyme is not known. Studies that address the transdifferentiation of renal stem cells into mature kidney are limited by a lack of known interactions that create signaling pathways. It is quite likely that steps towards terminal differentiation involve changes in protein expression in and around developing nephrons, and such changes are probably controlled by as yet undescribed genes. We hypothesize that the molecular programs determining pattern formation, spatial position, cell fate, phenotype, and structural differentiation are regulated by early sets of master genes responding to morphogenic cues. This hierarchy of genes is probably under the control of transcription factors expressing DNA- binding motifs, and the influence of these proteins over the fate of forming renal tissue is mediated through their linkage to other downstream genes producing organ differentiation. In this application we would like to identify new DNA-binding proteins that play a role in kidney development by their effects on transcription. We believe it is feasible to isolate and characterize several of these early regulatory genes using a favorite gene approach. There is evidence for the importance of zinc finger proteins in the development of nephrons in multiple species from flies forward. We propose to look for other new zinc fingers that are active in embryonic murine kidney. The murine system offers several advantages if one wishes to study higher vertebrates. Most importantly, we expect to determine the phenotype and function of some of these new finger genes by constructing targeted mutations as recombinant mice carrying null alleles, and eventually, by characterizing some of their interactions with other downstream genes. Such information will help establish new positional coordinates for transcriptional pathways in renal growth and maturation.