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Journal of Molecular Cell Biology Advance Access published online on September 30, 2009
Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjp028
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© The Author (2009). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Paracrine Unpaired Signaling through the JAK/STAT Pathway Controls Self-renewal and Lineage Differentiation of Drosophila Intestinal Stem Cells

Guonan Lin1,{dagger}, Na Xu1,2,{dagger} 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: xirongwen{at}nibs.ac.cn


  Abstract

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

{dagger} These authors contributed equally to this work.


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