Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract.

The murine genes, Foxc1 and Foxc2 (previously, Mf1 and Mfh1), encode forkhead/winged helix transcription factors with virtually identical DNA-binding domains and overlapping expression patterns in various embryonic tissues. Foxc1/Mf1 is disrupted in the mutant, congenital hydrocephalus (Foxc1/Mf1(ch)), which has multiple developmental defects. We show here that, depending on the genetic background, most Foxc1 homozygous mutants are born with abnormalities of the metanephric kidney, including duplex kidneys and double ureters, one of which is a hydroureter. Analysis of embryos reveals that Foxc1 homozygotes have ectopic mesonephric tubules and ectopic anterior ureteric buds. Moreover, expression in the intermediate mesoderm of Glial cell-derived neurotrophic factor (Gdnf), a primary inducer of the ureteric bud, is expanded more anteriorly in Foxc1 homozygous mutants compared with wild type. These findings support the hypothesis of Mackie and Stephens concerning the etiology of duplex kidney and hydroureter in human infants with congenital kidney abnormalities (Mackie, G. G. and Stephens, F. G. (1975) J. Urol. 114, 274-280). Previous studies established that most Foxc1(lacZ )Foxc2(tm1) compound heterozygotes have the same spectrum of cardiovascular defects as single homozygous null mutants, demonstrating interaction between the two genes in the cardiovascular system. Here, we show that most compound heterozygotes have hypoplastic kidneys and a single hydroureter, while all heterozygotes are normal. This provides evidence that the two genes interact in kidney as well as heart development.