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 forkhe ad/winged helix transcription factors with virtually identical DNA-binding domains and overlapping expression patterns in various embryonic tissues. F oxc1/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 Ford homozygous mutants are born with abnor malities of the metanephric kidney, including duplex kidneys and double ure ters, one of which is a hydroureter, Analysis of embryos reveals that Ford homozygotes have ectopic mesonephric tubules and ectopic anterior ureteric buds. Moreover, expression in the intermediate mesoderm of Glial cell-deriv ed neurotrophic factor (Gdnf), a primary inducer of the ureteric bud, is ex panded more anteriorly in Ford homozygous mutants compared with wild type. These findings support the hypothesis of Mackle 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) c ompound heterozygotes have the same spectrum of cardiovascular defects as s ingle homozygous null mutants, demonstrating interaction between the two ge nes in the cardiovascular system. Here, we show that most compound heterozy gotes have hypoplastic kidneys and a single hydroureter, while all heterozy gotes are normal. This provides evidence that the two genes interact in kid ney as well as heart development.