To maintain the integrity of the adult gut, the proliferation and differentiation of stem cells must be strictly controlled. Several signaling pathways control the proliferation and differentiation of Drosophila intestinal epithelial cells. Although the modulatory effects of insulin pathway components on cell proliferation have been characterized, their specific role in which cell type and how these components interact with other regulatory signaling pathways remain largely unclear. In this study, we found that InR/Pi3K has major functions in enteroblasts (EBs) that were not previously described. The absence of InR/Pi3K in progenitors leads to a decrease in the number of EBs, while it has no significant effect on intestinal stem cells (ISCs). In addition, we found that InR/Pi3K regulates Notch activity in ISCs and EBs in an opposite way. This is also the reason for the decrease in EB. On the one hand, aberrantly low levels of Notch signaling in ISCs inhibit their proper differentiation into EBs; on the other hand, the higher Notch levels in EBs promote their excessive differentiation into enterocytes (ECs), leading to marked increases in abnormal ECs and decreased proliferation. Moreover, we found that Upd/JAK/STAT signaling acts as an effector or modifier of InR/Pi3K function in the midgut and cooperates with EGFR signaling to regulate cell proliferation. Altogether, our results demonstrate that InR and Pi3K are essential for coordinating stem cell differentiation and proliferation to maintain intestinal homeostasis.

中文翻译：

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InR 和 Pi3K 通过成肠细胞中的 STAT/EGFR 和 Notch 信号维持肠道稳态

为了维持成体肠道的完整性，必须严格控制干细胞的增殖和分化。多种信号通路控制细胞的增殖和分化果蝇肠上皮细胞。尽管胰岛素途径成分对细胞增殖的调节作用已被表征，但它们在细胞类型中的具体作用以及这些成分如何与其他调节信号传导途径相互作用仍很大程度上不清楚。在这项研究中，我们发现 InR/Pi3K 在肠成细胞 (EB) 中具有以前未描述过的主要功能。祖细胞中InR/Pi3K的缺失会导致EB数量减少，但对肠干细胞（ISC）没有显着影响。此外，我们发现 InR/Pi3K 以相反的方式调节 ISC 和 EB 中的 Notch 活性。这也是EB下降的原因。一方面，ISC 中异常低水平的 Notch 信号抑制其正常分化为 EB；另一方面，EB中较高的Notch水平促进其过度分化为肠上皮细胞（EC），导致异常EC显着增加和增殖减少。此外，我们发现Upd/JAK/STAT信号传导作为中肠中InR/Pi3K功能的效应器或调节器，并与EGFR信号传导配合调节细胞增殖。总而言之，我们的结果表明 InR 和 Pi3K 对于协调干细胞分化和增殖以维持肠道稳态至关重要。