Cdx2 determines the fate of postnatal intestinal endoderm
Cdx2 determines the fate of postnatal intestinal endoderm
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DOI：
10.1242/dev.070722
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发表时间：
2012-02-01
期刊：
影响因子：
4.6
通讯作者：
Beck, Felix
中科院分区：
文献类型：
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作者：
Stringer, Emma J.;Duluc, Isabelle;Beck, Felix
敲除肠道Cdx2会产生不同的影响，这取决于发生这种情况的发育阶段。在发育早期，它在中肠产生组织学上有序的胃粘膜。成年小鼠肠上皮，特别是lgr5阳性干细胞中Cdx2的条件失活可以使动物长期存活，但不能产生这种表型。相反，内胚层细胞在肠道环境中表现出胃基因的细胞自主表达，而不伴有Barx1的中胚层表达，而Barx1是胃形态发生所必需的。cdx2阴性的内胚层细胞也不能表达Sox2， Sox2是胃形态发生的标志。因此，干细胞生态位的成熟似乎与表达正常胃发育所需的位置信息线索的能力丧失有关。cdx2阴性的肠隐窝产生表面下囊泡，而非靶向的隐窝肥大，随后取代表面上皮。这些观察结果得到了体外培养肠隐窝Cdx2失活研究的支持。这消除了它们形成长期生长的肠道类器官的能力，这些类器官可以分化成肠道表型。我们得出结论，Cdx2的表达对于肠道干细胞分化为任何肠道细胞类型至关重要，但它们保持一定程度的细胞自主可塑性，使它们能够开启各种胃基因。
Knock out of intestinal Cdx2 produces different effects depending upon the developmental stage at which this occurs. Early in development it produces histologically ordered stomach mucosa in the midgut. Conditional inactivation of Cdx2 in adult intestinal epithelium, as well as specifically in the Lgr5-positive stem cells, of adult mice allows long-term survival of the animals but fails to produce this phenotype. Instead, the endodermal cells exhibit cell-autonomous expression of gastric genes in an intestinal setting that is not accompanied by mesodermal expression of Barx1, which is necessary for gastric morphogenesis. Cdx2-negative endodermal cells also fail to express Sox2, a marker of gastric morphogenesis. Maturation of the stem cell niche thus appears to be associated with loss of ability to express positional information cues that are required for normal stomach development. Cdx2-negative intestinal crypts produce subsurface cystic vesicles, whereas untargeted crypts hypertrophy to later replace the surface epithelium. These observations are supported by studies involving inactivation of Cdx2 in intestinal crypts cultured in vitro. This abolishes their ability to form long-term growing intestinal organoids that differentiate into intestinal phenotypes. We conclude that expression of Cdx2 is essential for differentiation of gut stem cells into any of the intestinal cell types, but they maintain a degree of cell-autonomous plasticity that allows them to switch on a variety of gastric genes.