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Fig. 6. Human SPRY2 mediates its effect via Fgf genes and resembles the
phenotype induced by inhibition of the ERK/MAPK pathway. Although local
application of an agarose bead soaked with BSA, Fgf8 or Fgf10 (A,C,D) does not
alter Spry2 gene expression, a Fgf7-soaked bead (B) induces its
expression in culture when compared with the contralateral side that serves as
a control (arrow). The asterisk in D indicates the site of the bead. (E) The
kidney of a normal E11.5 embryo cultured for 48 hours shows an extensively
branched ureteric bud (indicated in orange) and induced nephrons (indicated in
green). (F) The kidney from an embryo expressing human SPRY2 has a
ureteric bud with less branching and no nephrons at this stage of culture. (G)
Quantification of the reduction in the degree of ureteric branching between
wild-type and human SPRY2 kidneys
(***P<0.005). A 48 hour culture. (H,K) Fgf7 and Gdnf,
when administered to the culture media, alone (H) or in combination (K;
Fgf2,7,10), lead to substantial recovery in the branching defect affecting the
ureteric buds of the kidneys expressing human SPRY2 (compare H,I,K,L
with F), whereas Fgf2 does not (J). Fgf7 signalling (H), a combination of
Fgf7, Fgf2 and Fgf10 signalling (K), and GDNF signalling (L) induce the
formation of supernumerary epithelial buds from the Wolffian duct (arrows),
indicating that human SPRY2 sensitizes the kidney to these signals.
(M) Quantification of the responses of human SPRY2 transgenic
kidneys. Significant differences (**P<0.05), numbers of
samples and growth factors analysed are indicated. Administration of PD98059,
an inhibitor of ERK/MAP kinase, reduces branching of the ureteric bud in a
normal kidney (compare N,O with E) and has an additive influence on the
reduction in ureteric elongation when human SPRY2 is expressed
(compare P,Q with F). Scale bar: 100 µm.
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