Molecular development of the kidney: A review of the results of gene disruption studies

Abstract

The kidney has been used for the last 50 years as a model system for the study of tissue inductions and vertebrate organogenesis. While much is known about the morphologic development of the kidney, it is only in the last few years that the molecular mechanisms involved in these processes have begun to be identified. This is largely a result of the identification of genes expressed during kidney development and the application of techniques for single gene disruption. Mammalian kidney development is described, and the methodology for single gene disruption is discussed. For a candidate gene to be unequivocally shown to be involved in organ development, three conditions are necessary. First, the gene must be spatially expressed correctly relative to the developing organ. Second, the gene has to be temporally expressed in a correct manner. Finally, when that gene is disrupted, normal organ development must not occur. There are now 11 genes that satisfy these conditions and thus have been shown to be crucial for metanephric kidney development: WT-1, Pax-2, c-ret, GDNF, alpha8beta1, Wnt-4, BF-2, BMP-7, PDGF B, PDGFRbeta, and alpha3beta1. These genes and their probable roles in kidney development are discussed, and some molecular pathways are suggested. Finally, the applications, limitations, and future trends in single gene disruption studies are discussed. Single gene disruption already has generated a wealth of information about kidney development and mammalian development in general. It is likely that this information is only the beginning, and many startling and profound discoveries can be expected in the years to come both from the utilization of knockout mice that already exist and those that will be created. (Am J Kidney Dis 1998 Mar;31(3):383-97)