Phases of canonical Wnt signaling during the development of mouse intestinal epithelium
Phases of canonical Wnt signaling during the development of mouse intestinal epithelium
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DOI：
10.1053/j.gastro.2007.04.072
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发表时间：
2007-08-01
期刊：
影响因子：
29.4
通讯作者：
Shivdasani, Ramesh A.
中科院分区：
文献类型：
--
作者：
Kim, Byeong-Moo;Mao, Junhao;Shivdasani, Ramesh A.
背景和目标：肠隐窝构成了一个小生境，其中上皮祖细胞对Wnt信号做出反应，复制并准备分化。由于Wnt通路基因突变导致肠癌，因此Wnt信号在肠道上皮稳态中的作用是一个深入研究的主题。我们研究了Wnt信号是如何在肠道发育过程中建立的。研究方法：我们研究了小鼠胚胎形成阶段Writ信号的时空特征，此时绒毛突起出现，隐窝前体占据绒毛间区域。我们使用TOP-GAL转基因小鼠和Axin 2（LacZ）小鼠，这些小鼠忠实地报告了典型的Wnt活性、相关分子标记和具有异常β-连环蛋白激活的胚胎。结果：发育中的肠在绒毛出现后首先显示Writ信号传导的证据。在绒毛形态发生过程中，绒毛间细胞增殖活跃，但缺乏经典Writ信号转导的迹象。令人惊讶的是，在妊娠后期和短暂的此后，明显的Wnt活性是明显的分化，有丝分裂后绒毛上皮。无论是Tcf 4，肠Writ信号的主要转录效应子，也不是候选Wnt靶CD 44和cyclinD 1在显示高Writ活性的晚期胎儿绒毛细胞中表达。相反，这些细胞表达相关因子Tcf 3和不同的Wnt靶点c-Myc。过早和失调的β-连环蛋白激活导致转基因小鼠严重的绒毛畸形。结论：Writ信号传导、上皮细胞增殖和组织分化之间的关系在发育和成年肠道中是逆转的。经典的Wnt通路在早期肠绒毛和成人隐窝中具有独立的，尽管可能重叠的功能。这些观察促进了对Writ在肠道发育和疾病中功能的理解。
Background & Aims: Intestinal crypts constitute a niche in which epithelial progenitors respond to Wnt signals, replicate, and prepare to differentiate. Because mutations in Wnt pathway genes lead to intestinal cancer, the role of Wnt signaling in gut epithelial homeostasis is a subject of intense investigation. We studied how Wnt signaling is established during intestine development. Methods: We studied spatiotemporal features of Writ signaling at formative stages in mouse embryos, when villous projections appear and crypt precursors occupy intervillus regions. We used TOP-GAL transgenic and Axin2(LacZ) mice, which report faithfully on canonical Wnt activity, relevant molecular markers, and embryos with aberrant beta-catenin activation. Results: Developing intestines first display evidence for Writ signaling after appearance of villi. During villus morphogenesis, intervillus cells proliferate actively but lack signs of canonical Writ signaling. Surprisingly, in late gestation and briefly thereafter, conspicuous Wnt activity is evident in differentiated, postmitotic villus epithelium. Neither Tcf4, a principal transcriptional effector of intestinal Writ signals, nor candidate Wnt targets CD44 and cyclinD1 are expressed in late fetal villus cells that show high Writ activity. Instead, those cells express the related factor Tcf3 and a different Wnt target, c-Myc. Premature and deregulated beta-catenin activation causes severe villus dysmorphogenesis in transgenic mice. Conclusions: Relationships among Writ signaling, epithelial proliferation, and tissue differentiation are reversed in the developing and adult gut. The canonical Wnt pathway has independent, albeit possibly overlapping, functions in early intestinal villi and adult crypts. These observations advance understanding of Writ functions in intestinal development and disease.