Paracrine Unpaired Signaling through the JAK/STAT Pathway Controls Self-renewal and Lineage Differentiation of Drosophila Intestinal Stem Cells
Paracrine Unpaired Signaling through the JAK/STAT Pathway Controls Self-renewal and Lineage Differentiation of Drosophila Intestinal Stem Cells
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DOI：
10.1093/jmcb/mjp028
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发表时间：
2010-02-01
影响因子：
5.5
通讯作者：
Xi, Rongwen
中科院分区：
文献类型：
--
作者：
Lin, Guonan;Xu, Na;Xi, Rongwen
果蝇和哺乳动物肠道干细胞（ISCs）在调节机制上有相似之处，它们都需要无翼(Wg)/Wnt信号来进行自我更新，尽管其他调节机制在很大程度上是未知的。在这里，我们发现Unpaired是另一个来自肌肉生态位的旁分泌信号，它激活了果蝇ISC中典型的JAK/STAT信号级联，以调节ISC的自我更新和分化。我们发现受损的JAK信号导致ISC静止和丢失，而信号过度激活产生额外的ISC样细胞和祖细胞。同时破坏或激活ISCs中的JAK和Wg信号分别导致更强的ISC丢失或更大的iscc样细胞扩增，而不是单独改变任何一条途径，表明这两条途径并行发挥作用。此外，我们发现JAK信号的缺失会导致肠母细胞分化受阻，而JAK信号的减少会优先影响肠内分泌（ee）细胞的分化。相反，JAK过度激活会产生额外分化的细胞，尤其是ee细胞。结合Notch (N)的功能分析，我们认为JAK/STAT信号在果蝇ISC谱系中有两个独立的作用：它在N上游与Wg信号并行和协同作用，控制ISC自我更新；并与N活性拮抗，控制肠道祖细胞的二元命运选择。
Drosophila and mammalian intestinal stem cells (ISCs) share similarities in their regulatory mechanisms, with both requiring Wingless (Wg)/Wnt signaling for their self-renewal, although additional regulatory mechanisms are largely unknown. Here we report the identification of Unpaired as another paracrine signal from the muscular niche, which activates a canonical JAK/STAT signaling cascade in Drosophila ISCs to regulate ISC self-renewal and differentiation. We show that compromised JAK signaling causes ISC quiescence and loss, whereas signaling overactivation produces extra ISC-like and progenitor cells. Simultaneous disruption or activation of both JAK and Wg signaling in ISCs results in a stronger ISC loss or a greater expansion of ISC-like cells, respectively, than by altering either pathway alone, indicating that the two pathways function in parallel. Furthermore, we show that loss of JAK signaling causes blockage of enteroblast differentiation and reduced JAK signaling preferentially affects enteroendocrine (ee) cell differentiation. Conversely, JAK overactivation produces extra differentiated cells, especially ee cells. Together with the functional analysis with Notch (N), we suggest two separate roles of JAK/STAT signaling in Drosophila ISC lineages: it functions upstream of N, in parallel and cooperatively with Wg signaling to control ISC self-renewal; it also antagonizes with N activity to control the binary fate choice of intestinal progenitor cells.