FGFR3 contributes to intestinal crypt cell growth arrest.
Fibroblast growth factors (FGFs) are important regulators of the dynamic development and turnover of tissues. Among FGF receptors, FGFR3 expression is confined in the intestinal crypts. We examined FGFR3-deficient mice and saw increased intestinal crypt depth but no change in villae length or in the distribution of differentiated intestinal cells, suggesting that the impact of lack of FGFR3 was limited to the progenitor cell compartment. Accordingly, enhancement of intestinal crypt proliferation was observed in FGFR3 mutant mice and interestingly, upon anti-FGFR3 antibody administration in wild type mice. Moreover, injection of FGF18, a ligand of FGFR3, in wild type mice resulted in decreased cell proliferation within the intestinal crypts. In addition, we found that ERK level of activation was increased in FGFR3-deficient intestinal epithelium. In vitro studies showed that ERK, AKT and activation was regulated by FGFs and that ERK level of activation was inversely correlated to FGFR3 level of expression in the intestinal crypt cells. Furthermore, effects of FGF18 on ERK and AKT activation paralleled FGFR3 effects on these intracellular targets. Our data indicate that FGF18 and FGFR3 are involved, possibly as partners, in the control of intestinal precursor cell proliferation.
Arnaud-Dabernat
Sandrine
S
Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Yadav
Deepak
D
Sarvetnick
Nora
N
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D048430:Cell Shape; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases