Fibroblast growth receptors (FGFRs) consist of four signaling family members. Mice with deletions of fgfr1 or fgfr2 are embryonic lethal prior to the onset of kidney development. To determine roles of FGFR1 and FGFR2 in the ureteric bud, we used a conditional targeting approach. First, we generated transgenic mice using the Hoxb7 promoter to drive cre recombinase and green fluorescent protein expression throughout ureteric bud tissue. We crossed Hoxb7creEGFP mice with mice carrying lox-p sites flanking critical regions of fgfr1 and/or fgfr2. Absence of fgfr1 from the ureteric bud (fgfr1(UB-/-)) results in no apparent renal abnormalities. In contrast, fgfr2(UB-/-) mice have very aberrant ureteric bud branching, thin ureteric bud stalks, and fewer ureteric bud tips. Fgfr2(UB-/-) ureteric bud tips also demonstrate inappropriate regions of apoptosis and reduced proliferation. The nephrogenic mesenchymal lineage in fgfr2(UB-/-) mice develops normal-appearing glomeruli and tubules, and only slightly fewer nephrons than controls. In contrast, fgfr2(UB-/-) kidneys have abnormally thickened subcapsular cortical stromal mesenchyme. Ultimately, fgfr2(UB-/-) adult kidneys are small and abnormally shaped or are hydronephrotic. Finally, there are no additional abnormalities in the fgfr1/2(UB-/-) kidneys versus the fgfr2(UB-/-) kidneys. In conclusion, FGFR2, but not FGFR1, appears crucial for ureteric bud branching morphogenesis and stromal mesenchyme patterning.

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.

Expression of SSTR3, SSTR4, and SSTR5 in mouse proximal tubules complements the expression of SSTR1 and SSTR2 in collecting ducts as seen in other species. Taken together, the kidney is one of few organs expressing all five somatostatin receptors outside of the nervous system and pancreas.

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In embryonic kidneys, SRIF is expressed first at the interface of the metanephric mesenchyme and basolateral ureteric bud and later in maturing thin descending limbs of Henle. Expression in the thin descending limb persists in the adult kidney.