Progress in gene targeting: using mutant mice to study renal function and disease

Genetic engineering in mice has provided much information about gene function in renal health and disease. This knowledge has largely come from conventional transgenic approaches. Recently, methods have been developed to control the cell type, timing and reversibility of target gene expression. Advances in identifying promoters conferring renal cell-specific gene regulation in vivo have greatly facilitated interpretation of gene targeting studies. Site-specific recombinases have permitted cell-specific knockout of genes; Cre is the preeminent recombinase, but recent progress with other recombinases, include Flp and PhiC31, will likely increase the usefulness of this class of enzymes. Temporally regulated gene expression, particularly using doxycycline- and tamoxifen-inducible systems, holds great promise for avoiding developmental effects of gene mutations as well as facilitating comparison of the same animal's phenotype before and after gene modification. RNA interference is undergoing tremendous growth and has great potential for achieving gene knockdown quickly and reversibly. To date, however, the utility of these systems in modifying renal function in transgenic mice remains unproven. Finally, new gene targeting tools are in development that may substantially simplify generation of transgenic animals. This review discusses the state-of-the-art in gene targeting in the kidney, reviewing function, indications and limitations of the molecular biologic tools.