Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan.
PLoS One. 2013;8(3):e58310. doi: 10.1371/journal.pone.0058310. Epub 2013 Mar 6.
There are four cell lineages derived from intestinal stem cells that are located at the crypt and villus in the mammalian intestine the non-secretory absorptive enterocytes, and the secretory cells, which include mucous-secreting goblet cells, regulatory peptide-secreting enteroendocrine cells and antimicrobial peptide-secreting Paneth cells. Although fibroblast growth factor (Fgf) signaling is important for cell proliferation and differentiation in various tissues, its role in intestinal differentiation is less well understood.
METHODOLOGY/PRINCIPAL FINDINGS: We used a loss of function approach to investigate the importance of Fgf signaling in intestinal cell differentiation in zebrafish; abnormal differentiation of goblet cells was observed when Fgf signaling was inhibited using SU5402 or in the Tg(hsp70ldnfgfr1-EGFP) transgenic line. We identified Fgfr2c as an important receptor for cell differentiation. The number of goblet cells and enteroendocrine cells was reduced in fgfr2c morphants. In addition to secretory cells, enterocyte differentiation was also disrupted in fgfr2c morphants. Furthermore, proliferating cells were increased in the morphants. Interestingly, the loss of fgfr2c expression repressed secretory cell differentiation and increased cell proliferation in the mib(ta52b) mutant that had defective Notch signaling.
CONCLUSIONS/SIGNIFICANCE: In conclusion, we found that Fgfr2c signaling derived from mesenchymal cells is important for regulating the differentiation of zebrafish intestine epithelial cells by promoting cell cycle exit. The results of Fgfr2c knockdown in mib(ta52b) mutants indicated that Fgfr2c signaling is required for intestinal cell differentiation. These findings provide new evidences that Fgf signaling is required for the differentiation of intestinal cells in the zebrafish developing gut.
哺乳动物肠道中的肠干细胞可分化为位于隐窝和绒毛处的四个细胞谱系：非分泌性吸收性肠上皮细胞，以及分泌细胞，包括分泌黏液的杯状细胞、分泌调节肽的肠内分泌细胞和分泌抗菌肽的潘氏细胞。尽管成纤维细胞生长因子（Fgf）信号对于各种组织中的细胞增殖和分化很重要，但它在肠道分化中的作用还不太清楚。
方法/主要发现：我们使用功能丧失的方法研究了 Fgf 信号在斑马鱼肠道细胞分化中的重要性；当使用 SU5402 抑制 Fgf 信号或在 Tg(hsp70ldnfgfr1-EGFP)转基因系中抑制 Fgf 信号时，观察到杯状细胞的分化异常。我们确定 Fgfr2c 是细胞分化的一个重要受体。在 fgfr2c 形态发生缺陷型中，杯状细胞和肠内分泌细胞的数量减少。除了分泌细胞，肠上皮细胞的分化也在 fgfr2c 形态发生缺陷型中受到破坏。此外，在形态发生缺陷型中增殖细胞增加。有趣的是，fgfr2c 表达的缺失抑制了 mib(ta52b)突变体中 secretory cell 分化，该突变体 Notch 信号缺陷。
总之，我们发现来自间质细胞的 Fgfr2c 信号通过促进细胞周期退出，对于调节斑马鱼肠道上皮细胞的分化很重要。在 mib(ta52b)突变体中进行 Fgfr2c 敲低的结果表明，Fgfr2c 信号对于肠道细胞分化是必需的。这些发现为 Fgf 信号对于斑马鱼肠道中肠道细胞分化是必需的提供了新的证据。
