Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme.

To determine the importance of fibroblast growth factor receptors (fgfrs) 1 and 2 in the metanephric mesenchyme, we generated conditional knockout mice (fgfr(Mes-/-)). Fgfr1(Mes-/-) and fgfr2(Mes-/-) mice develop normal-appearing kidneys. Deletion of both receptors (fgfr1/2(Mes-/-)) results in renal aplasia. Fgfr1/2(Mes-/-) mice develop a ureteric bud (and occasionally an ectopic bud) that does not elongate or branch, and the mice do not develop an obvious metanephric mesenchyme. By in situ hybridization, regions of mutant mesenchyme near the ureteric bud(s) express Eya1 and Six1, but not Six2, Sall1, or Pax2, while the ureteric bud expresses Ret and Pax2 normally. Abnormally high rates of apoptosis and relatively low rates of proliferation are present in mutant mesenchyme dorsal to the mutant ureteric bud at embryonic day (E) 10.5, while mutant ureteric bud tissues undergo high rates of apoptosis by E11.5. Thus, fgfr1 and fgfr2 together are critical for normal formation of metanephric mesenchyme. While the ureteric bud(s) initiates, it does not elongate or branch infgfr1/2(Mes-/-) mice. In metanephric mesenchymal rudiments, fgfr1 and fgfr2 appear to function downstream of Eya1 and Six1, but upstream of Six2, Sall1, and Pax2. Finally, this is the first example of renal aplasia in a conditional knockout model.