Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production
Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production
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DOI：
10.1242/dev.02252
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发表时间：
2006-03-01
期刊：
影响因子：
4.6
通讯作者：
Carlsson, P
中科院分区：
文献类型：
--
作者：
Ormestad, M;Astorga, J;Carlsson, P
脊椎动物肠道的发育是由内胚层上皮和内脏中胚层之间的旁分泌相互作用控制的。在成人中，相同类型的信号控制上皮细胞增殖和存活，这说明了基质在结肠癌进展中的重要性。在这里，我们表明，针对鼠Foxf 1和Foxf 2，编码叉头转录因子，具有多效性的影响肠道旁分泌信号。两个Foxf 2等位基因或Foxf 1和Foxf 2各一个等位基因的失活导致一系列缺陷，包括巨结肠、结肠直肠肌肉发育不全和无神经节细胞症。FOXF在内脏中胚层的表达被上皮分泌的Indian和Sonic Hedgehog激活。在Foxf突变体中，Bmp 4的间充质表达减少，而Wnt 5a表达增加。上皮细胞中β-连环蛋白核定位的经典Wnt通路的激活与过度增殖和抗凋亡相关。细胞外基质，特别是胶原蛋白，在Foxf突变肠中严重减少，这导致上皮去极化和组织崩解。因此，Foxf蛋白是控制上皮细胞增殖和存活的间充质因子，并将hedgehog与Bmp和Wnt信号传导联系起来。
Development of the vertebrate gut is controlled by paracrine crosstalk between the endodermal epithelium and the associated splanchnic mesoderm. in the adult, the same types of signals control epithelial proliferation and survival, which account for the importance of the stroma in colon carcinoma progression. Here, we show that targeting murine Foxf1 and Foxf2, encoding forkhead transcription factors, has pleiotropic effects on intestinal paracrine signaling. Inactivation of both Foxf2 alleles, or one allele each of Foxf1 and Foxf2, cause a range of defects, including megacolon, colorectal muscle hypoplasia and agangliosis. Foxf expression in the splanchnic mesoderm is activated by Indian and sonic hedgehog secreted by the epithelium. In Foxf mutants, mesenchymal expression of Bmp4 is reduced, whereas Wnt5a expression is increased. Activation of the canonical Wnt pathway with nuclear localization of beta-catenin in epithelial cells - is associated with over-proliferation and resistance to apoptosis. Extracellular matrix, particularly collagens, is severely reduced in Foxf mutant intestine, which causes epithelial depolarization and tissue disintegration. Thus, Foxf proteins are mesenchymal factors that control epithelial proliferation and survival, and link hedgehog to Bmp and Wnt signaling.