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Transient Scute activation via a self-stimulatory loop directs enteroendocrine cell pair specification from self-renewing intestinal stem cells

Nature Cell Biology volume 20, pages 152–161 (2018)Cite this article

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Abstract

The process through which multiple types of cell-lineage-restricted progenitor cells are specified from multipotent stem cells is unclear. Here we show that, in intestinal stem cell lineages in adult Drosophila, in which the Delta-Notch-signalling-guided progenitor cell differentiation into enterocytes is the default mode, the specification of enteroendocrine cells (EEs) is initiated by transient Scute activation in a process driven by transcriptional self-stimulation combined with a negative feedback regulation between Scute and Notch targets. Scute activation induces asymmetric intestinal stem cell divisions that generate EE progenitor cells. The mitosis-inducing and fate-inducing activities of Scute guide each EE progenitor cell to divide exactly once prior to its terminal differentiation, yielding a pair of EEs. The transient expression of a fate inducer therefore specifies both type and numbers of committed progenitor cells originating from stem cells, which could represent a general mechanism used for diversifying committed progenitor cells from multipotent stem cells.

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Fig. 1: An EE-regeneration model reveals that ISCs self-renew during the generation of EE pairs.
Fig. 2: Transient Sc expression precedes EE generation from ISCs.
Fig. 3: Notch mutant ISCs have increased Sc expression and only generate EE cells.
Fig. 4: Sc functions as both a mitogenic factor and a cell-fate inducer.
Fig. 5: Process of sc-overexpression-induced EE generation from ISCs.
Fig. 6: Sc induces E(spl) genes in ISCs.
Fig. 7: Regulatory feedback loops control Sc expression in ISCs.

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  • 19 April 2018

    In the version of this Article originally published, the author had misnumbered the reference citations in the Methods, using numbers 1–14 instead of 46–59. These errors have now been corrected in all online versions of the Article.

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Acknowledgements

The authors thank the members of the fly community, as identified in the Methods, for providing fly stocks and antibodies, the Bloomington Drosophila Stock Center, the Tsinghua Fly Center and the Developmental Studies Hybridoma Bank (DSHB) for reagents, and A. Spradling, J. Rajagopal and members of the Xi laboratory for critical reading, and J. Snyder for proofreading the manuscript. This work was supported by the National Key Research and Development Program of China (2017YFA0103602 to R.X), the National Basic Research Program of China (2014CB850002 and 2011CB812700 to R.X.) and the National Natural Science Foundation of China (31501105 to N.X.).

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Authors and Affiliations

  1. Graduate School of Peking Union Medical College, Beijing, China

    Jun Chen & Rongwen Xi

  2. National Institute of Biological Sciences, Beijing, China

    Jun Chen, Na Xu, Chenhui Wang, Pin Huang, Huanwei Huang, Zhen Jin, Tao Cai & Rongwen Xi

  3. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Zhongsheng Yu & Renjie Jiao

  4. Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China

    Renjie Jiao

  5. Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

    Rongwen Xi

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Conceptualization was provided by J.C. and R.X. Methodology was designed by J.C., N.X., C.W., P.H., Z.J., H.H., Z.Y., T.C., R.J. and R.X. Investigations were carried out by J.C., N.X., C.W., P.H., H.H. and R.X. Formal analysis was performed by J.C., N.X., C.W., P.H., Z.J., H.H. and R.X. The manuscript was written by J.C., H.H. and R.X.

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Correspondence to Rongwen Xi.

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Chen, J., Xu, N., Wang, C. et al. Transient Scute activation via a self-stimulatory loop directs enteroendocrine cell pair specification from self-renewing intestinal stem cells. Nat Cell Biol 20, 152–161 (2018). https://doi.org/10.1038/s41556-017-0020-0

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