Developmental anomalies of the kidneys and urinary tract are common, occurring in 10% of the population. Severe congenital effects lead to death or lifelong morbidity, while the more common milder anomalies can predispose to infection, stone formation and chronic renal failure, leading to their diagnosis later in life. A better understanding of the molecular mechanisms which regulate the morphogenesis of the kidneys and ureters is essential for the development of new strategies for the treatment and prevention of these congenital disorders. Interactions between mesenchyme and epithelia are important for the development of the kidney as well as other epithelial tissues. Furthermore, these interactions have also been shown to be important in tumor progression and cancer metastasis. The function of the renal stromal mesenchyme in kidney development has been poorly understood, in part due to the lack of an early embryonic marker of the stromal cell lineage. Recent work to identify and characterize a novel member of the Winged-Helix family of transcription factors, BF-2, has demonstrated that it is a specific early marker of stromal mesenchyme. Targeted disruption of the BF-2 gene in mice leads to severe anomalies of the kidneys and ureters. Differentiation of the nephrogenic mesenchyme is inhibited, as is the growth and branching of the collecting system and growth of the ureter. These studies suggested that interactions between the stromal mesenchyme and the developing epithelial components of the kidney are essential in kidney morphogenesis. Furthermore, the putative transcription factor, BF-2, is likely to regulate the expression of the molecules which mediate these interactions. Thus the overall Specific Aims are: 1) to identify the stage in the differentiation of the nephron which is inhibited in the BF-2 mutant and to measure the rate of proliferation of the ureteric epithelium; 2) to demonstrate the stromal cells produce essential factors by rescuing the BF-2 mutant phenotype in vitro with wild-type stromal cells; and 3) to identify targets of BF-2 which mediate inductive interactions between the stroma and the epithelia.
