Arnaud-Dabernat Sandrine, Yadav Deepak, Sarvetnick Nora
Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
J Cell Physiol. 2008 Jul;216(1):261-8. doi: 10.1002/jcp.21401.
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.
成纤维细胞生长因子（FGFs）是组织动态发育和更新的重要调节因子。在FGF受体中，FGFR3的表达局限于肠隐窝。我们研究了FGFR3基因缺失的小鼠，发现肠隐窝深度增加，但绒毛长度或分化肠细胞的分布没有变化，这表明缺乏FGFR3的影响仅限于祖细胞区室。因此，在FGFR3突变小鼠中观察到肠隐窝增殖增强，有趣的是，在野生型小鼠中给予抗FGFR3抗体后也出现了这种情况。此外，在野生型小鼠中注射FGFR3的配体FGF18导致肠隐窝内细胞增殖减少。此外，我们发现FGFR3基因缺失的肠上皮中ERK的激活水平增加。体外研究表明，ERK、AKT的激活受FGFs调节，并且ERK的激活水平与肠隐窝细胞中FGFR3的表达水平呈负相关。此外，FGF18对ERK和AKT激活的影响与FGFR3对这些细胞内靶点的影响相似。我们的数据表明，FGF18和FGFR3可能作为伙伴参与肠道前体细胞增殖的控制。
