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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1
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Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1

机译：Dickkopf-1腺病毒表达揭示Wnt信号在成年小肠和结肠增殖中的基本要求

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Whereas the adult gastrointestinal epithelium undergoes tremendous self-renewal through active proliferation in crypt stem cell compartments, the responsible growth factors regulating this continuous proliferation have not been defined. The exploration of physiologic functions of Wnt proteins in adult organisms has been hampered by functional redundancy and the necessity for conditional inactivation strategies. Dickkopf-1 (Dkk1) is a potent secreted Wnt antagonist that interacts with Wnt coreceptors of the LRP family. To address the contribution of Wnt signaling to gastrointestinal epithelial proliferation, adenoviral expression of Dkk1 was used to achieve stringent, conditional, and reversible Wnt inhibition in adult animals. Adenovirus Dkk1 (Ad Dkk1) treatment of adult mice repressed expression of the Wnt target genes CD44 and EphB2 within 2 days in both small intestine and colon, indicating an extremely broad role for Wnt signaling in the maintenance of adult gastrointestinal gene expression. In parallel. Ad Dkk1 markedly inhibited proliferation in small intestine and colon, accompanied by progressive architectural degeneration with the loss of crypts, villi, and glandular structure by 7 days. Whereas decreased Dkk1 expression at later time points (>10 days) was followed by crypt and villus regeneration, which was consistent with a reversible process, substantial mortality ensued from colitis and systemic infection. These results indicate the efficacy of systemic expression of secreted Wnt antagonists as a general strategy for conditional inactivation of Wnt signaling in adult organisms and illustrate a striking reliance on a single growth factor pathway for the maintenance of the architecture of the adult small intestine and colon.
机译：尽管成人胃肠道上皮细胞通过隐窝干细胞区室的活跃增殖而经历了巨大的自我更新，但尚未定义调节这种持续增殖的负责任的生长因子。 Wnt蛋白在成年生物中的生理功能的探索已被功能冗余和条件灭活策略的必要性所阻碍。 Dickkopf-1（Dkk1）是一种有效的Wnt拮抗剂，可与LRP家族的Wnt核心受体相互作用。为了解决Wnt信号对胃肠道上皮细胞增殖的作用，Dkk1的腺病毒表达被用来在成年动物中实现严格的，有条件的和可逆的Wnt抑制作用。腺病毒Dkk1（Ad Dkk1）对成年小鼠的治疗在2天之内抑制了小肠和结肠中Wnt靶基因CD44和EphB2的表达，表明Wnt信号在维持成年胃肠道基因表达中发挥着极其广泛的作用。在平行下。 Ad Dkk1显着抑制小肠和结肠的增殖，伴随进行性建筑退化，并在7天之内丧失隐窝，绒毛和腺结构。 Dkk1表达在随后的时间点（> 10天）下降，然后发生隐窝和绒毛再生，这与可逆过程一致，结肠炎和全身感染导致大量死亡。这些结果表明，分泌型Wnt拮抗剂的系统表达作为在成年生物中Wnt信号条件性失活的一般策略是有效的，并说明了对单一生长因子途径的显着依赖，以维持成年小肠和结肠的结构。

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