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PMID: 21068063 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration.

Development (Cambridge, England) ·Vol. 137 ·No. 24 ·2010-12-00 ·Pages 4147-58

Shaw RL, Kohlmaier A, Polesello C, Veelken C, Edgar BA, Tapon N

Abstract

Intestinal stem cells (ISCs) in the adult Drosophila midgut proliferate to self-renew and to produce differentiating daughter cells that replace those lost as part of normal gut function. Intestinal stress induces the activation of Upd/Jak/Stat signalling, which promotes intestinal regeneration by inducing rapid stem cell proliferation. We have investigated the role of the Hippo (Hpo) pathway in the Drosophila intestine (midgut). Hpo pathway inactivation in either the ISCs or the differentiated enterocytes induces a phenotype similar to that observed under stress situations, including increased stem cell proliferation and expression of Jak/Stat pathway ligands. Hpo pathway targets are induced by stresses such as bacterial infection, suggesting that the Hpo pathway functions as a sensor of cellular stress in the differentiated cells of the midgut. In addition, Yki, the pro-growth transcription factor target of the Hpo pathway, is required in ISCs to drive the proliferative response to stress. Our results suggest that the Hpo pathway is a mediator of the regenerative response in the Drosophila midgut.

MeSH Terms
Animals Cell Proliferation Drosophila Proteins/genetics,metabolism Drosophila melanogaster/cytology,growth & development Female Intestines/cytology Intracellular Signaling Peptides and Proteins/genetics,metabolism Microscopy, Fluorescence Protein Serine-Threonine Kinases/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/genetics,physiology Stem Cells/cytology,metabolism Temperature
Chemicals
Drosophila Proteins Intracellular Signaling Peptides and Proteins Protein Serine-Threonine Kinases hpo protein, Drosophila
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Shaw Rachael L
Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
Kohlmaier Alexander
Polesello Cédric
Veelken Cornelia
Edgar Bruce A
Tapon Nicolas
References (60)
60 references, click to expand
  1. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded.
    Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10532-7 PMID: 20498073
  2. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila.
    Genes Dev. 2009 Oct 1;23(19):2333-44 PMID: 19797770
  3. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase.
    Development. 1995 Apr;121(4):1053-63 PMID: 7743921
  4. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control.
    Nat Rev Genet. 2006 May;7(5):349-59 PMID: 16619050
  5. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila.
    Development. 2002 Dec;129(24):5719-30 PMID: 12421711
  6. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms.
    Curr Biol. 2010 Apr 13;20(7):573-81 PMID: 20362447
  7. Elucidation of a universal size-control mechanism in Drosophila and mammals.
    Cell. 2007 Sep 21;130(6):1120-33 PMID: 17889654
  8. Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury.
    Dev Cell. 2003 Sep;5(3):441-50 PMID: 12967563
  9. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila.
    Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15810-5 PMID: 20798049
  10. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo.
    Gene Expr Patterns. 2007 Jan;7(3):323-31 PMID: 17008134
  11. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis.
    Nat Cell Biol. 2006 Jan;8(1):27-36 PMID: 16341207
  12. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis.
    Neuron. 1999 Mar;22(3):451-61 PMID: 10197526
  13. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway.
    Nat Cell Biol. 2003 Oct;5(10):914-20 PMID: 14502294
  14. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network.
    Nat Rev Cancer. 2007 Mar;7(3):182-91 PMID: 17318211
  15. Genome-wide RNAi screen identifies genes involved in intestinal pathogenic bacterial infection.
    Science. 2009 Jul 17;325(5938):340-3 PMID: 19520911
  16. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila.
    Nat Cell Biol. 2003 Oct;5(10):921-7 PMID: 14502295
  17. Transcriptional control of stem cell maintenance in the Drosophila intestine.
    Development. 2010 Mar;137(5):705-14 PMID: 20147375
  18. Regulation of leg size and shape by the Dachsous/Fat signalling pathway during regeneration.
    Development. 2009 Jul;136(13):2235-45 PMID: 19474149
  19. Identification of genes required for Drosophila eye development using a phenotypic enhancer-trap.
    Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9220-5 PMID: 9256463
  20. Basolateral junctions utilize warts signaling to control epithelial-mesenchymal transition and proliferation crucial for migration and invasion of Drosophila ovarian epithelial cells.
    Genetics. 2008 Apr;178(4):1947-71 PMID: 18430928
  21. The intestinal epithelial stem cell.
    Bioessays. 2002 Jan;24(1):91-8 PMID: 11782954
  22. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut.
    Cell. 2009 Jun 26;137(7):1343-55 PMID: 19563763
  23. Searching for adult stem cells in the intestine.
    EMBO Mol Med. 2009 Aug;1(5):255-9 PMID: 20049728
  24. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut.
    Cell Stem Cell. 2008 Oct 9;3(4):442-55 PMID: 18940735
  25. Stem cell regulation by JAK/STAT signaling in Drosophila.
    Semin Cell Dev Biol. 2008 Aug;19(4):407-13 PMID: 18603010
  26. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling.
    Science. 2007 Feb 16;315(5814):988-92 PMID: 17303754
  27. JAK-STAT is restrained by Notch to control cell proliferation of the Drosophila intestinal stem cells.
    J Cell Biochem. 2010 Apr 1;109(5):992-9 PMID: 20082318
  28. The molecular cloning and characterization of Drosophila melanogaster myosin-IA and myosin-IB.
    J Mol Biol. 1994 Jun 10;239(3):347-56 PMID: 8201616
  29. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation.
    Cell Host Microbe. 2009 Feb 19;5(2):200-11 PMID: 19218090
  30. A model Notch response element detects Suppressor of Hairless-dependent molecular switch.
    Curr Biol. 2001 Jan 9;11(1):60-4 PMID: 11166182
  31. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.
    Genes Dev. 2007 Nov 1;21(21):2747-61 PMID: 17974916
  32. Ajuba LIM proteins are negative regulators of the Hippo signaling pathway.
    Curr Biol. 2010 Apr 13;20(7):657-62 PMID: 20303269
  33. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts.
    Cell. 2003 Aug 22;114(4):445-56 PMID: 12941273
  34. The WW domain protein Kibra acts upstream of Hippo in Drosophila.
    Dev Cell. 2010 Feb 16;18(2):309-16 PMID: 20159600
  35. Spatiotemporal rescue of memory dysfunction in Drosophila.
    Science. 2003 Dec 5;302(5651):1765-8 PMID: 14657498
  36. In vivo regulation of Yorkie phosphorylation and localization.
    Development. 2008 Mar;135(6):1081-8 PMID: 18256197
  37. Upstream regulation of the hippo size control pathway.
    Curr Biol. 2010 Jul 13;20(13):R574-82 PMID: 20619814
  38. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded.
    Dev Cell. 2010 Feb 16;18(2):288-99 PMID: 20159598
  39. Adenomatous polyposis coli regulates Drosophila intestinal stem cell proliferation.
    Development. 2009 Jul;136(13):2255-64 PMID: 19502486
  40. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded.
    Curr Biol. 2010 Apr 13;20(7):582-90 PMID: 20362445
  41. JAK/STAT signaling coordinates stem cell proliferation and multilineage differentiation in the Drosophila intestinal stem cell lineage.
    Dev Biol. 2010 Feb 1;338(1):28-37 PMID: 19896937
  42. The adult Drosophila posterior midgut is maintained by pluripotent stem cells.
    Nature. 2006 Jan 26;439(7075):470-4 PMID: 16340960
  43. Self-renewal and cancer of the gut: two sides of a coin.
    Science. 2005 Mar 25;307(5717):1904-9 PMID: 15790842
  44. JAK/STAT signalling in Drosophila: insights into conserved regulatory and cellular functions.
    Development. 2006 Jul;133(14):2605-16 PMID: 16794031
  45. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP.
    Cell. 2005 Aug 12;122(3):421-34 PMID: 16096061
  46. Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation.
    Curr Biol. 2010 Sep 14;20(17):1580-7 PMID: 20727758
  47. Kibra is a regulator of the Salvador/Warts/Hippo signaling network.
    Dev Cell. 2010 Feb 16;18(2):300-8 PMID: 20159599
  48. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway.
    Nat Cell Biol. 2009 Dec;11(12):1444-50 PMID: 19935651
  49. Evidence that stem cells reside in the adult Drosophila midgut epithelium.
    Nature. 2006 Jan 26;439(7075):475-9 PMID: 16340959
  50. The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis.
    Genes Dev. 2003 Oct 15;17(20):2514-9 PMID: 14561774
  51. Notch signals control the fate of immature progenitor cells in the intestine.
    Nature. 2005 Jun 16;435(7044):964-8 PMID: 15959516
  52. salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.
    Cell. 2002 Aug 23;110(4):467-78 PMID: 12202036
  53. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats.
    Cell. 2005 Mar 11;120(5):675-85 PMID: 15766530
  54. Tissue damage-induced intestinal stem cell division in Drosophila.
    Cell Stem Cell. 2009 Jan 9;4(1):49-61 PMID: 19128792
  55. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis.
    Cell. 2003 Aug 22;114(4):457-67 PMID: 12941274
  56. Drosophila host defense after oral infection by an entomopathogenic Pseudomonas species.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11414-9 PMID: 16061818
  57. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.
    Nature. 2005 Jun 16;435(7044):959-63 PMID: 15959515
  58. YAP1 increases organ size and expands undifferentiated progenitor cells.
    Curr Biol. 2007 Dec 4;17(23):2054-60 PMID: 17980593
  59. Clonal analysis of mouse intestinal epithelial progenitors.
    Gastroenterology. 1999 Jan;116(1):7-14 PMID: 9869596
  60. Signaling pathways in intestinal development and cancer.
    Annu Rev Cell Dev Biol. 2004;20:695-723 PMID: 15473857
Article Info
Journal
Development (Cambridge, England)
Abbr.
Development
ISSN
1477-9129
DOI
10.1242/dev.052506
Published
2010-12-00
Epub
2010-00-10
Pages
4147-58
Language
English
Region
England
NLM ID
8701744
PMCID
PMC2990206
Subset
IM
Grants
NIGMS NIH HHS · R01 GM051186 · United States
NIGMS NIH HHS · GM51186 · United States
Cancer Research UK · United Kingdom
External Links
PubMed source DOI: 10.1242/dev.052506 PMC Full Text View journal details
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