NIBS袭荣文实验室续写Nature成果 干细胞分化机制

　　

生物通报道，NIBS袭荣文实验室在《Journal of Molecular Cell Biology》杂志上在线发表题为“Paracrine Unpaired signaling through the JAK/STAT pathway controls self-renewal and lineage differentiation of Drosophila intestinal stem cells”的文章。该文章揭示了果蝇肠上皮干细胞自我更新与定向分化的新机制。

 

这是袭荣文博士继08年在Nature发表肠上皮干细胞分化机制文章后的又一研究新进展。博士生林国南和徐娜（我所与北师大联合培养）为该论文的共同第一作者，袭荣文博士为本文通讯作者。此项研究为科技部863和北京市科委资助课题，在北京生命科学研究所完成。

 

成体干细胞对维持组织的再生和修复能力起重要作用。而其调控的紊乱也可能直接导致肿瘤等疾病的发生。因此全面理解干细胞的自我更新及分化的调控机制有重要意义。近年来在果蝇的肠道中的肠上皮干细胞逐渐成为一个作为研究成体干细胞调节机制的模式系统。已知Wnt/Wg 信号通路以旁分泌的形式促进肠上皮干细胞的自我更新，但其它的调控机制尚不清楚。

 

在这篇论文中，作者发现另一个信号通路，名为JAK/STAT 通路，也以旁分泌的形式维持着干细胞的自我更新。在肠上皮干细胞中抑制该通路引起干细胞的活性下降和进一步的分化，从而导致干细胞的丢失。同时抑制JAK/STAT 和Wnt通路可以加重干细胞的丢失，提示这两条信号通路以平行的方式共同维持着肠上皮干细胞的自我更新。该研究也揭示了JAK/STAT通路对干细胞下游分化过程中的作用。抑制该通路的活性导致细胞停留在不完全分化状态，而过度激活该通路导致过多的分泌型细胞的产生。通过与Notch的功能关系的研究，作者提出JAK/STAT 与Notch的拮抗作用决定了吸收型或分泌型细胞分化方向的选择。因此，该文章不但揭示了果蝇肠上皮干细胞自我更新的一个新的机制，也进一步揭示了肠上皮细胞分化过程中的命运抉择机制。该发现将有助于进一步理解肠道干细胞的调节机制及肠道肿瘤等疾病的发生机制。

 

生物通推荐原文检索

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

 

* Correspondence to: Rongwen Xi, E-mail: [e-mail]

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.

 

Keywords: intestinal stem cell, Drosophila, the JAK/STAT pathway, Wingless signaling, self-renewal and differentiation, enterocyte, enteroendocrine cell

 

Received July 21, 2009; Revised August 24, 2009; Accepted September 1, 2009