2009年9月30日，北京生命科學(xué)研究所襲榮文實(shí)驗(yàn)室在Journal of Molecular Cell Biology雜志上在線發(fā)表題為“Paracrine Unpaired signaling through the JAK/STAT pathway controls self-renewal and lineage differentiation of Drosophila intestinal stem cells”的文章,。該文章揭示了果蠅腸上皮干細(xì)胞自我更新與定向分化的新機(jī)制,。
成體干細(xì)胞對(duì)維持組織的再生和修復(fù)能力起重要作用,。而其調(diào)控的紊亂也可能直接導(dǎo)致腫瘤等疾病的發(fā)生。因此全面理解干細(xì)胞的自我更新及分化的調(diào)控機(jī)制有重要意義,。近年來在果蠅的腸道中的腸上皮干細(xì)胞逐漸成為一個(gè)作為研究成體干細(xì)胞調(diào)節(jié)機(jī)制的模式系統(tǒng),。已知Wnt/Wg 信號(hào)通路以旁分泌的形式促進(jìn)腸上皮干細(xì)胞的自我更新，但其它的調(diào)控機(jī)制尚不清楚,。在這篇論文中,，作者發(fā)現(xiàn)另一個(gè)信號(hào)通路，名為JAK/STAT 通路,，也以旁分泌的形式維持著干細(xì)胞的自我更新,。在腸上皮干細(xì)胞中抑制該通路引起干細(xì)胞的活性下降和進(jìn)一步的分化，從而導(dǎo)致干細(xì)胞的丟失,。同時(shí)抑制JAK/STAT 和Wnt通路可以加重干細(xì)胞的丟失,，提示這兩條信號(hào)通路以平行的方式共同維持著腸上皮干細(xì)胞的自我更新。該研究也揭示了JAK/STAT通路對(duì)干細(xì)胞下游分化過程中的作用,。抑制該通路的活性導(dǎo)致細(xì)胞停留在不完全分化狀態(tài),，而過度激活該通路導(dǎo)致過多的分泌型細(xì)胞的產(chǎn)生。通過與Notch的功能關(guān)系的研究,，作者提出JAK/STAT 與Notch的拮抗作用決定了吸收型或分泌型細(xì)胞分化方向的選擇,。因此，該文章不但揭示了果蠅腸上皮干細(xì)胞自我更新的一個(gè)新的機(jī)制,，也進(jìn)一步揭示了腸上皮細(xì)胞分化過程中的命運(yùn)抉擇機(jī)制。該發(fā)現(xiàn)將有助于進(jìn)一步理解腸道干細(xì)胞的調(diào)節(jié)機(jī)制及腸道腫瘤等疾病的發(fā)生機(jī)制,。（生物谷Bioon.com）
生物谷推薦原始出處：
Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjp028
Paracrine Unpaired Signaling through the JAK/STAT Pathway Controls Self-renewal and Lineage Differentiation of Drosophila Intestinal Stem Cells
Guonan Lin1,, Na Xu1,2, and Rongwen Xi1,*
1 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
2 College of Life Sciences, Beijing Normal University, Beijing 100875, China
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.
