Lee Wen-Chih, Beebe Katherine, Sudmeier Lisa, Micchelli Craig A
Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
Development. 2009 Jul;136(13):2255-64. doi: 10.1242/dev.035196.
Adult stem cells define a cellular reserve with the unique capacity to replenish differentiated cells of a tissue throughout an organism's lifetime. Previous analysis has demonstrated that the adult Drosophila midgut is maintained by a population of multipotent intestinal stem cells (ISCs) that resides in epithelial niches. Adenomatous polyposis coli (Apc), a tumor suppressor gene conserved in both invertebrates and vertebrates, is known to play a role in multiple developmental processes in Drosophila. Here, we examine the consequences of eliminating Apc function on adult midgut homeostasis. Our analysis shows that loss of Apc results in the disruption of midgut homeostasis and is associated with hyperplasia and multilayering of the midgut epithelium. A mosaic analysis of marked ISC cell lineages demonstrates that Apc is required specifically in ISCs to regulate proliferation, but is not required for ISC self-renewal or the specification of cell fate within the lineage. Cell autonomous activation of Wnt signaling in the ISC lineage phenocopied Apc loss and Apc mutants were suppressed in an allele-specific manner by abrogating Wnt signaling, suggesting that the effects of Apc are mediated in part by the Wnt pathway. Together, these data underscore the essential requirement of Apc in exerting regulatory control over stem cell activity, as well as the consequences that disrupting this regulation can have on tissue homeostasis.
成体干细胞定义了一种细胞储备库，具有在生物体整个生命周期中补充组织分化细胞的独特能力。先前的分析表明，成年果蝇中肠由位于上皮微环境中的一群多能肠干细胞（ISC）维持。腺瘤性息肉病大肠杆菌（Apc）是一种在无脊椎动物和脊椎动物中都保守的肿瘤抑制基因，已知在果蝇的多个发育过程中发挥作用。在这里，我们研究消除Apc功能对成年中肠稳态的影响。我们的分析表明，Apc的缺失导致中肠稳态的破坏，并与中肠上皮的增生和多层化有关。对标记的ISC细胞谱系进行的镶嵌分析表明，Apc在ISC中是调节增殖所必需的，但对于ISC的自我更新或谱系内细胞命运的特化不是必需的。ISC谱系中Wnt信号的细胞自主激活模拟了Apc缺失的表型，并且通过废除Wnt信号以等位基因特异性方式抑制了Apc突变体，这表明Apc的作用部分是由Wnt途径介导的。总之，这些数据强调了Apc对干细胞活性进行调节控制的基本要求，以及破坏这种调节对组织稳态可能产生的后果。
