Zfh2 controls progenitor cell activation and differentiation in the adult Drosophila intestinal absorptive lineage

Autoři: Sebastian E. Rojas Villa aff001;  Fanju W. Meng aff002;  Benoît Biteau aff002
Působiště autorů: Department of Biology, University of Rochester, Rochester, New York, United States of America aff001;  Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America aff002
Vyšlo v časopise: Zfh2 controls progenitor cell activation and differentiation in the adult Drosophila intestinal absorptive lineage. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008553
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008553


Many tissues rely on resident stem cell population to maintain homeostasis. The balance between cell proliferation and differentiation is critical to permit tissue regeneration and prevent dysplasia, particularly following tissue damage. Thus, understanding the cellular processes and genetic programs that coordinate these processes is essential. Here, we report that the conserved transcription factor zfh2 is specifically expressed in Drosophila adult intestinal stem cell and progenitors and is a critical regulator of cell differentiation in this lineage. We show that zfh2 expression is required and sufficient to drive the activation of enteroblasts, the non-proliferative progenitors of absorptive cells. This transition is characterized by the transient formation of thin membrane protrusions, morphological changes characteristic of migratory cells and compensatory stem cell proliferation. We found that zfh2 acts in parallel to insulin signaling and upstream of the TOR growth-promoting pathway during early differentiation. Finally, maintaining zfh2 expression in late enteroblasts blocks terminal differentiation and leads to the formation of highly dysplastic lesions, defining a new late cell differentiation transition. Together, our study greatly improves our understanding of the cascade of cellular changes and regulatory steps that control differentiation in the adult fly midgut and identifies zfh2 as a major player in these processes.

Klíčová slova:

Cell differentiation – Differentiated tumors – Drosophila melanogaster – Gastrointestinal tract – Insulin signaling – Stem cells – Transcription factors – TOR signaling


1. Neumuller R.A. and Knoblich J.A., Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes Dev, 2009. 23(23): p. 2675–99. doi: 10.1101/gad.1850809 19952104

2. Micchelli C.A. and Perrimon N., Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature, 2006. 439(7075): p. 475–9. doi: 10.1038/nature04371 16340959

3. Ohlstein B. and Spradling A., The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature, 2006. 439(7075): p. 470–4. doi: 10.1038/nature04333 16340960

4. Biteau B. and Jasper H., Slit/Robo Signaling Regulates Cell Fate Decisions in the Intestinal Stem Cell Lineage of Drosophila. Cell Rep, 2014. 7(6): p. 1867–75. doi: 10.1016/j.celrep.2014.05.024 24931602

5. Amcheslavsky A., Jiang J., and Ip Y.T., Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell, 2009. 4(1): p. 49–61. doi: 10.1016/j.stem.2008.10.016 19128792

6. Buchon N., et al., Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Cell Host Microbe, 2009. 5(2): p. 200–11. doi: 10.1016/j.chom.2009.01.003 19218090

7. Chatterjee M. and Ip Y.T., Pathogenic stimulation of intestinal stem cell response in Drosophila. J Cell Physiol, 2009. 220(3): p. 664–71. doi: 10.1002/jcp.21808 19452446

8. Jiang H., et al., Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell, 2009. 137(7): p. 1343–55. doi: 10.1016/j.cell.2009.05.014 19563763

9. Amcheslavsky A., et al., Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J Cell Biol, 2011. 193(4): p. 695–710. doi: 10.1083/jcb.201103018 21555458

10. Kapuria S., et al., Notch-Mediated Suppression of TSC2 Expression Regulates Cell Differentiation in the Drosophila Intestinal Stem Cell Lineage. PLoS Genet, 2012. 8(11): p. e1003045. doi: 10.1371/journal.pgen.1003045 23144631

11. Choi N.H., Lucchetta E., and Ohlstein B., Nonautonomous regulation of Drosophila midgut stem cell proliferation by the insulin-signaling pathway. Proc Natl Acad Sci U S A, 2011. 108(46): p. 18702–7. doi: 10.1073/pnas.1109348108 22049341

12. Xiang J., et al., EGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration. Nat Commun, 2017. 8: p. 15125. doi: 10.1038/ncomms15125 28485389

13. Antonello Z.A., et al., Robust intestinal homeostasis relies on cellular plasticity in enteroblasts mediated by miR-8-Escargot switch. EMBO J, 2015. 34(15): p. 2025–41. doi: 10.15252/embj.201591517 26077448

14. Zhai Z., et al., Accumulation of differentiating intestinal stem cell progenies drives tumorigenesis. Nat Commun, 2015. 6: p. 10219. doi: 10.1038/ncomms10219 26690827

15. Chen J., et al., A feedback amplification loop between stem cells and their progeny promotes tissue regeneration and tumorigenesis. Elife, 2016. 5.

16. Lai Z.C., Fortini M.E., and Rubin G.M., The embryonic expression patterns of zfh-1 and zfh-2, two Drosophila genes encoding novel zinc-finger homeodomain proteins. Mech Dev, 1991. 34(2–3): p. 123–34. doi: 10.1016/0925-4773(91)90049-c 1680377

17. Terriente J., et al., The Drosophila gene zfh2 is required to establish proximal-distal domains in the wing disc. Dev Biol, 2008. 320(1): p. 102–12. doi: 10.1016/j.ydbio.2008.04.028 18571155

18. Perea D., et al., Multiple roles of the gene zinc finger homeodomain-2 in the development of the Drosophila wing. Mech Dev, 2013. 130(9–10): p. 467–81. doi: 10.1016/j.mod.2013.06.002 23811114

19. Guarner A., et al., The zinc finger homeodomain-2 gene of Drosophila controls Notch targets and regulates apoptosis in the tarsal segments. Dev Biol, 2014. 385(2): p. 350–65. doi: 10.1016/j.ydbio.2013.10.011 24144920

20. Lundell M.J. and Hirsh J., The zfh-2 gene product is a potential regulator of neuron-specific dopa decarboxylase gene expression in Drosophila. Dev Biol, 1992. 154(1): p. 84–94. doi: 10.1016/0012-1606(92)90050-q 1426635

21. Helenius I.T., et al., Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen. J Immunol, 2016. 196(2): p. 655–667. doi: 10.4049/jimmunol.1501708 26643480

22. Sun X., et al., Deletion of atbf1/zfhx3 in mouse prostate causes neoplastic lesions, likely by attenuation of membrane and secretory proteins and multiple signaling pathways. Neoplasia, 2014. 16(5): p. 377–89. doi: 10.1016/j.neo.2014.05.001 24934715

23. Zhang Z., et al., ATBF1-a messenger RNA expression is correlated with better prognosis in breast cancer. Clin Cancer Res, 2005. 11(1): p. 193–8. 15671546

24. Cho Y.G., et al., Genetic alterations of the ATBF1 gene in gastric cancer. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4355–9.

25. Sun X., et al., Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer. Nat Genet, 2005. 37(4): p. 407–12. doi: 10.1038/ng1528 15750593

26. Hemmi K., et al., A homeodomain-zinc finger protein, ZFHX4, is expressed in neuronal differentiation manner and suppressed in muscle differentiation manner. Biol Pharm Bull, 2006. 29(9): p. 1830–5. doi: 10.1248/bpb.29.1830 16946494

27. Qing T., et al., Somatic mutations in ZFHX4 gene are associated with poor overall survival of Chinese esophageal squamous cell carcinoma patients. Sci Rep, 2017. 7(1): p. 4951. doi: 10.1038/s41598-017-04221-7 28694483

28. Buchon N., et al., Morphological and molecular characterization of adult midgut compartmentalization in Drosophila. Cell Rep, 2013. 3(5): p. 1725–38. doi: 10.1016/j.celrep.2013.04.001 23643535

29. Doupe D.P., et al., Drosophila intestinal stem and progenitor cells are major sources and regulators of homeostatic niche signals. Proc Natl Acad Sci U S A, 2018.

30. Ohlstein B. and Spradling A., Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science, 2007. 315(5814): p. 988–92. doi: 10.1126/science.1136606 17303754

31. Calleja M., et al., Visualization of gene expression in living adult Drosophila. Science, 1996. 274(5285): p. 252–5. doi: 10.1126/science.274.5285.252 8824191

32. Zhai Z., Boquete J.P., and Lemaitre B., A genetic framework controlling the differentiation of intestinal stem cells during regeneration in Drosophila. PLoS Genet, 2017. 13(6): p. e1006854. doi: 10.1371/journal.pgen.1006854 28662029

33. Evans C.J., et al., G-TRACE: rapid Gal4-based cell lineage analysis in Drosophila. Nat Methods, 2009. 6(8): p. 603–5. doi: 10.1038/nmeth.1356 19633663

34. Biteau B., et al., Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet, 2010. 6(10): p. e1001159. doi: 10.1371/journal.pgen.1001159 20976250

35. O'Brien L.E., et al., Altered modes of stem cell division drive adaptive intestinal growth. Cell, 2011. 147(3): p. 603–14. doi: 10.1016/j.cell.2011.08.048 22036568

36. Yamashita Y.M., Inaba M., and Buszczak M., Specialized Intercellular Communications via Cytonemes and Nanotubes. Annu Rev Cell Dev Biol, 2018. 34: p. 59–84. doi: 10.1146/annurev-cellbio-100617-062932 30074816

37. Perdigoto C.N., Schweisguth F., and Bardin A.J., Distinct levels of Notch activity for commitment and terminal differentiation of stem cells in the adult fly intestine. Development, 2011. 138(21): p. 4585–95. doi: 10.1242/dev.065292 21965616

38. Korzelius J., et al., Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells. EMBO J, 2014. 33(24): p. 2967–82. doi: 10.15252/embj.201489072 25298397

39. Martin J.L., et al., Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of division, differentiation and loss. Elife, 2018. 7.

40. Jung C.G., et al., Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation. Development, 2005. 132(23): p. 5137–45. doi: 10.1242/dev.02098 16251211

41. Sun X., et al., Characterization of nuclear localization and SUMOylation of the ATBF1 transcription factor in epithelial cells. PLoS One, 2014. 9(3): p. e92746. doi: 10.1371/journal.pone.0092746 24651376

42. Zhang S., et al., AT motif binding factor 1 (ATBF1) is highly phosphorylated in embryonic brain and protected from cleavage by calpain-1. Biochem Biophys Res Commun, 2012. 427(3): p. 537–41. doi: 10.1016/j.bbrc.2012.09.092 23022192

43. Meng F.W. and Biteau B., A Sox Transcription Factor Is a Critical Regulator of Adult Stem Cell Proliferation in the Drosophila Intestine. Cell Rep, 2015. 13(5): p. 906–14. doi: 10.1016/j.celrep.2015.09.061 26565904

44. Schindelin J., et al., Fiji: an open-source platform for biological-image analysis. Nat Methods, 2012. 9(7): p. 676–82. doi: 10.1038/nmeth.2019 22743772

Genetika Reprodukční medicína

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PLOS Genetics

2019 Číslo 12

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