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• W1989388426 abstract "Long-term maintenance of tissue homeostasis relies on the accurate regulation of somatic stem cell activity. Somatic stem cells have to respond to tissue damage and proliferate according to tissue requirements while avoiding overproliferation. The regulatory mechanisms involved in these responses are now being unraveled in the intestinal epithelium of Drosophila, providing new insight into strategies and mechanisms of stem cell regulation in barrier epithelia. Here, we review these studies and highlight recent findings in vertebrate epithelia that indicate significant conservation of regenerative strategies between vertebrate and fly epithelia. Long-term maintenance of tissue homeostasis relies on the accurate regulation of somatic stem cell activity. Somatic stem cells have to respond to tissue damage and proliferate according to tissue requirements while avoiding overproliferation. The regulatory mechanisms involved in these responses are now being unraveled in the intestinal epithelium of Drosophila, providing new insight into strategies and mechanisms of stem cell regulation in barrier epithelia. Here, we review these studies and highlight recent findings in vertebrate epithelia that indicate significant conservation of regenerative strategies between vertebrate and fly epithelia. Precise control of somatic stem cell (SC) activity is essential to the maintenance of tissue homeostasis in multicellular organisms. To ensure efficient replacement of damaged cells while limiting the potential for cancer, the proliferation rate of stem and progenitor cells has to be closely linked to tissue demands at any given time. This complex regulation, in which SCs integrate local and systemic cues with cell-intrinsic maintenance mechanisms, is only beginning to be understood. Unraveling these signaling mechanisms is likely to not only provide insight into basic mechanisms of SC regulation, but to also elucidate the molecular etiology of tissue dysfunction, including age-related degeneration and cancer (Radtke and Clevers, 2005Radtke F. Clevers H. Self-renewal and cancer of the gut: two sides of a coin.Science. 2005; 307: 1904-1909Crossref PubMed Scopus (414) Google Scholar, Rossi et al., 2008Rossi D.J. Jamieson C.H.M. Weissman I.L. Stems cells and the pathways to aging and cancer.Cell. 2008; 132: 681-696Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, Sharpless and DePinho, 2007Sharpless N.E. DePinho R.A. How stem cells age and why this makes us grow old.Nat. Rev. Mol. Cell Biol. 2007; 8: 703-713Crossref PubMed Scopus (334) Google Scholar). Indeed, characterization and genetic manipulation of selected SC populations in the mouse has demonstrated that the precise control of SC proliferation is crucial to prevent tumor formation (Barker et al., 2009Barker N. Ridgway R.A. van Es J.H. van de Wetering M. Begthel H. van den Born M. Danenberg E. Clarke A.R. Sansom O.J. Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer.Nature. 2009; 457: 608-611Crossref PubMed Scopus (532) Google Scholar, Lapouge et al., 2011Lapouge G. Youssef K.K. Vokaer B. Achouri Y. Michaux C. Sotiropoulou P.A. Blanpain C. Identifying the cellular origin of squamous skin tumors.Proc. Natl. Acad. Sci. USA. 2011; 108: 7431-7436Crossref PubMed Scopus (55) Google Scholar, White et al., 2011White A.C. Tran K. Khuu J. Dang C. Cui Y. Binder S.W. Lowry W.E. Defining the origins of Ras/p53-mediated squamous cell carcinoma.Proc. Natl. Acad. Sci. USA. 2011; 108: 7425-7430Crossref PubMed Scopus (39) Google Scholar, Youssef et al., 2010Youssef K.K. Van Keymeulen A. Lapouge G. Beck B. Michaux C. Achouri Y. Sotiropoulou P.A. Blanpain C. Identification of the cell lineage at the origin of basal cell carcinoma.Nat. Cell Biol. 2010; 12: 299-305Crossref PubMed Scopus (0) Google Scholar), and the identification of molecular similarities between cancer SCs and tissue-specific SCs further supports this notion (Merlos-Suarez et al., 2011Merlos-Suarez A. Barriga F.M. Jung P. Iglesias M. Cespedes M.V. Rossell D. Sevillano M. Hernando-Momblona X. da Silva-Diz V. Munoz P. et al.The Intestinal Stem Cell Signature Identifies Colorectal Cancer Stem Cells and Predicts Disease Relapse.Cell Stem Cell. 2011; 8: 511-524Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Different stem and progenitor cell populations display remarkable diversity in their proliferative behavior. This diversity presumably reflects the different regenerative requirements of individual tissues, and allows SCs to be classified into distinct categories (Figure 1): (1) continuously cycling SCs of high-turnover tissues, such as intestinal SCs (Li and Clevers, 2010Li L. Clevers H. Coexistence of quiescent and active adult stem cells in mammals.Science. 2010; 327: 542-545Crossref PubMed Scopus (324) Google Scholar, Simons and Clevers, 2011Simons B.D. Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues.Cell. 2011; 145: 851-862Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, van der Flier and Clevers, 2009van der Flier L.G. Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium.Annu. Rev. Physiol. 2009; 71: 241-260Crossref PubMed Scopus (321) Google Scholar) and short-term hematopoietic stem cells (HSCs) (Fuchs, 2009Fuchs E. The tortoise and the hair: slow-cycling cells in the stem cell race.Cell. 2009; 137: 811-819Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar); (2) SCs whose proliferative activity can be strongly induced by injury, including airway-basal epithelial SCs and muscle satellite cells (Abou-Khalil and Brack, 2010Abou-Khalil R. Brack A.S. Muscle stem cells and reversible quiescence: the role of sprouty.Cell Cycle. 2010; 9: 2575-2580PubMed Google Scholar, Dhawan and Rando, 2005Dhawan J. Rando T.A. Stem cells in postnatal myogenesis: molecular mechanisms of satellite cell quiescence, activation and replenishment.Trends Cell Biol. 2005; 15: 666-673Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, Rock and Hogan, 2011Rock J.R. Hogan B.L. Epithelial Progenitor Cells in Lung Development, Maintenance, Repair, and Disease.Annu. Rev. Cell Dev. Biol. 2011; 27: 493-512Crossref PubMed Scopus (68) Google Scholar); and (3) SCs with alternate quiescent and proliferative periods, such as hair follicle SCs (Fuchs, 2009Fuchs E. The tortoise and the hair: slow-cycling cells in the stem cell race.Cell. 2009; 137: 811-819Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). While distinct, these categories may not necessarily reflect intrinsic qualitative differences in SC regulation, because all SC populations display significant proliferative plasticity. The mouse intestine, for example, has a very rapid turnover rate, requiring Lgr5+ SCs in the small intestine to divide once every 24 hr to 48 hr (Barker et al., 2007Barker N. van Es J.H. Kuipers J. Kujala P. van den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007Crossref PubMed Scopus (1174) Google Scholar, Snippert et al., 2010Snippert H.J. van der Flier L.G. Sato T. van Es J.H. van den Born M. Kroon-Veenboer C. Barker N. Klein A.M. van Rheenen J. Simons B.D. Clevers H. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells.Cell. 2010; 143: 134-144Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar), but proliferation in the intestinal crypt can still be further increased in response to injury and infection (Liu et al., 2010cLiu X. Lu R. Wu S. Sun J. Salmonella regulation of intestinal stem cells through the Wnt/beta-catenin pathway.FEBS Lett. 2010; 584: 911-916Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, Saleh and Elson, 2011Saleh M. Elson C.O. Experimental inflammatory bowel disease: insights into the host-microbiota dialog.Immunity. 2011; 34: 293-302Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, Seno et al., 2009Seno H. Miyoshi H. Brown S.L. Geske M.J. Colonna M. Stappenbeck T.S. Efficient colonic mucosal wound repair requires Trem2 signaling.Proc. Natl. Acad. Sci. USA. 2009; 106: 256-261Crossref PubMed Scopus (58) Google Scholar). Similarly, in the bone marrow, long-term HSCs can undergo a reversible transition from quiescence to self-renewal (He et al., 2009He S. Nakada D. Morrison S.J. Mechanisms of stem cell self-renewal.Annu. Rev. Cell Dev. Biol. 2009; 25: 377-406Crossref PubMed Scopus (133) Google Scholar, Wilson et al., 2008Wilson A. Laurenti E. Oser G. van der Wath R.C. Blanco-Bose W. Jaworski M. Offner S. Dunant C.F. Eshkind L. Bockamp E. et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar), while the mouse trachea and muscle satellite cells display a low turnover rate in homeostasis, but dramatically increase their proliferative activity in response to injury (Dhawan and Rando, 2005Dhawan J. Rando T.A. Stem cells in postnatal myogenesis: molecular mechanisms of satellite cell quiescence, activation and replenishment.Trends Cell Biol. 2005; 15: 666-673Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, Rock and Hogan, 2011Rock J.R. Hogan B.L. Epithelial Progenitor Cells in Lung Development, Maintenance, Repair, and Disease.Annu. Rev. Cell Dev. Biol. 2011; 27: 493-512Crossref PubMed Scopus (68) Google Scholar, Shea et al., 2010Shea K.L. Xiang W. LaPorta V.S. Licht J.D. Keller C. Basson M.A. Brack A.S. Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration.Cell Stem Cell. 2010; 6: 117-129Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). These similarities suggest that the proliferative plasticity of different SC populations may be regulated by common mechanisms. To maintain homeostasis in mitotically active tissues, SC activity has to be controlled at several levels: (1) steady-state SC proliferation and self-renewal, as well as differentiation, to ensure long-term maintenance of a pluripotent SC pool; (2) acute induction of SC proliferation in response to tissue damage; and (3) reentry into a quiescent or nonproliferative state after the tissue has been repaired or regenerated. The complexity of somatic SC lineages in mammals often causes difficulties in definitively characterizing the regulation of these processes at the SC level in vivo, however, because transit amplifying cell populations exist in most regenerative tissues and because SCs are not definitively identified in all organs. The lineage relationship between different groups of multipotent cell populations in the mouse intestinal epithelium, for example, remains under investigation. Two populations of cells, Bmi1+ “+4” cells and Lgr5+ Crypt Base Columnar cells, were found to be able to fully regenerate the intestinal epithelium (Barker et al., 2007Barker N. van Es J.H. Kuipers J. Kujala P. van den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007Crossref PubMed Scopus (1174) Google Scholar, Sangiorgi and Capecchi, 2008Sangiorgi E. Capecchi M.R. Bmi1 is expressed in vivo in intestinal stem cells.Nat. Genet. 2008; 40: 915-920Crossref PubMed Scopus (408) Google Scholar). A recent study demonstrates that a hierarchy exists in this lineage, and that Lgr5+ SCs are dispensable for epithelial homeostasis in the villus. Interestingly, Bmi1+ cells, which constitute a more quiescent cell population, are capable of replenishing the Lgr5+ population in response to high regenerative demand (Tian et al., 2011Tian H. Biehs B. Warming S. Leong K.G. Rangell L. Klein O.D. de Sauvage F.J. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable.Nature. 2011; 478: 255-259Crossref PubMed Scopus (173) Google Scholar). Whether the proliferation rate of these two SC populations is regulated by similar or distinct mechanisms remains largely unexplored. Characterization of SC plasticity in simpler model organisms in which lineage relationships are clearly defined is thus expected to provide important conceptual and mechanistic insight into the maintenance of tissue homeostasis. Recent findings in Drosophila have provided such a model. Adult somatic SCs have been identified in the fly gonad, the intestine, and the malpighian tubules (Decotto and Spradling, 2005Decotto E. Spradling A.C. The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals.Dev. Cell. 2005; 9: 501-510Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, Fox and Spradling, 2009Fox D.T. Spradling A.C. The Drosophila hindgut lacks constitutively active adult stem cells but proliferates in response to tissue damage.Cell Stem Cell. 2009; 5: 290-297Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, Gönczy and DiNardo, 1996Gönczy P. DiNardo S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis.Development. 1996; 122: 2437-2447PubMed Google Scholar, Margolis and Spradling, 1995Margolis J. Spradling A. Identification and behavior of epithelial stem cells in the Drosophila ovary.Development. 1995; 121: 3797-3807PubMed Google Scholar, Micchelli and Perrimon, 2006Micchelli C.A. Perrimon N. Evidence that stem cells reside in the adult Drosophila midgut epithelium.Nature. 2006; 439: 475-479Crossref PubMed Scopus (281) Google Scholar, Ohlstein and Spradling, 2006Ohlstein B. Spradling A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells.Nature. 2006; 439: 470-474Crossref PubMed Scopus (291) Google Scholar, Singh et al., 2007Singh S.R. Liu W. Hou S.X. The adult Drosophila malpighian tubules are maintained by multipotent stem cells.Cell Stem Cell. 2007; 1: 191-203Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, Takashima et al., 2008Takashima S. Mkrtchyan M. Younossi-Hartenstein A. Merriam J.R. Hartenstein V. The behaviour of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling.Nature. 2008; 454: 651-655Crossref PubMed Scopus (71) Google Scholar). Among these SC populations, Intestinal SCs (ISCs) of the posterior midgut display remarkable proliferative plasticity and similarity to mammalian epithelial SC populations (Casali and Batlle, 2009Casali A. Batlle E. Intestinal stem cells in mammals and Drosophila.Cell Stem Cell. 2009; 4: 124-127Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Due to the advanced genetic tools available and the speed of genetic analysis, the exploration of molecular mechanisms regulating ISC function in flies has been extraordinarily rapid and comprehensive. An integrated model for epithelial SC regulation is thus emerging that is beginning to guide similar analysis in vertebrates. Here, we review the findings in the Drosophila system, highlighting emerging concepts as well as similarities and differences with vertebrate SC systems. The Drosophila midgut displays functional and morphological similarities with the mammalian small intestine, as well as with other vertebrate barrier epithelia. It consists of a simple columnar epithelium that is surrounded by visceral muscle, but in contrast to the mammalian intestine is not organized into crypts and villi (Figure 1). Consistent with this simpler overall structure, it is also composed of a limited number of cell types: large and polyploid EnteroCytes (ECs), the main absorptive cells in the epithelium; several types of small diploid EnteroEndocrine cells (EEs), which secrete different hormones (including tachykinin or allatostatin); and the common progenitors of these cells, the ISCs and their diploid daughter cells, EnteroBlasts (EBs). ISCs can be identified within the epithelium by their expression of the Notch ligand Delta (Dl) and the transcription factor escargot (esg). In young, healthy guts, EBs also express esg, but not Dl, while expressing Notch signaling reporters. EEs, in turn, are the only intestinal cells expressing the transcription factor prospero (pros), and ECs express the transcription factor Pdm-1. The ISC lineage was first characterized by Micchelli and Perrimon and by Ohlstein and Spradling (Micchelli and Perrimon, 2006Micchelli C.A. Perrimon N. Evidence that stem cells reside in the adult Drosophila midgut epithelium.Nature. 2006; 439: 475-479Crossref PubMed Scopus (281) Google Scholar, Ohlstein and Spradling, 2006Ohlstein B. Spradling A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells.Nature. 2006; 439: 470-474Crossref PubMed Scopus (291) Google Scholar). Both labs employed somatic recombination to trace cell lineages in the adult posterior midgut, and thus conclusively demonstrated that ISCs represent a multipotent SC population that resides basally in the intestinal epithelium and that gives rise to all cell types of the epithelium. Importantly, these studies also showed that the Drosophila intestinal epithelium lacks a transit amplifying cell population, in that EBs directly differentiate into EEs or ECs. This fact allows direct quantification of SC mitotic activity in this tissue (commonly detected using antibodies against phosphorylated Histone H3), because the only dividing cells detectable in the posterior midgut are ISCs. Signaling events regulating homeostatic proliferation in epithelial tissues of mammals have been extensively studied, yet the cell-specific requirements for individual signaling events remain unclear. In the intestine, for example, Wnt signaling, Notch signaling, and BMP signaling all promote proliferation, but also influence differentiation in the crypt (Crosnier et al., 2006Crosnier C. Stamataki D. Lewis J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control.Nat. Rev. Genet. 2006; 7: 349-359Crossref PubMed Scopus (260) Google Scholar, van der Flier and Clevers, 2009van der Flier L.G. Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium.Annu. Rev. Physiol. 2009; 71: 241-260Crossref PubMed Scopus (321) Google Scholar). Whether these effects are primarily a consequence of influencing SC proliferation or transit amplifying cell proliferation, however, remains unclear. In flies, the availability of lineage-tracing techniques for lineages derived from homozygous mutant SCs has allowed characterizing the signaling requirements for homeostatic proliferation of ISCs in detail, and has led to the emerging concept that signaling mechanisms ensuring homeostatic proliferation and signaling events inducing proliferation in response to injury are distinct. Drosophila ISCs are mostly slow-proliferating or nonproliferating in young, unchallenged intestines, but become highly proliferative after an environmental challenge or tissue injury. The existence of a “quiescent” state for ISCs has been under some debate: lineage tracing in ISCs had initially led to the impression that ISCs are continuously dividing cells, because once induced, clones appear to grow linearly, then enter a steady state where production of new cells seems to be in balance with the turnover rate of ECs (Ohlstein and Spradling, 2006Ohlstein B. Spradling A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells.Nature. 2006; 439: 470-474Crossref PubMed Scopus (291) Google Scholar). This interpretation is complicated, however, by mitotic and S-phase labeling experiments, which indicate long periods of very limited ISC proliferation in young, healthy guts. BrdU incorporation, for example, is observed in only 5%–10% of all ISCs in a 48 hr window (Hochmuth et al., 2011Hochmuth C.E. Biteau B. Bohmann D. Jasper H. Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila.Cell Stem Cell. 2011; 8: 188-199Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). A low basal level of tissue renewal has been revealed, on the other hand, by separate lineage tracing studies. In these, a “Flp-out” strategy was used to induce heritable GFP expression in all ISCs and their progeny in adulthood, demonstrating that the whole tissue is turned over in about 2 weeks in females and in over 1 month in males (Jiang et al., 2009Jiang H. Patel P.H. Kohlmaier A. Grenley M.O. McEwen D.G. Edgar B.A. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut.Cell. 2009; 137: 1343-1355Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). This corresponds to total tissue turnover of about 4 times in females and twice in males over the whole lifespan of the animal. This basal homeostatic proliferation and self-renewal of ISCs requires the activity of several growth factor signaling pathways (Figure 2). Using the MARCM method (Lee and Luo, 1999Lee T. Luo L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis.Neuron. 1999; 22: 451-461Abstract Full Text Full Text PDF PubMed Google Scholar) to induce homozygosity for mutations in the EGF Receptor (EGFR) and the Insulin Receptor (InR), it was shown that the growth factor response pathways activated by these receptors are essential for ISC proliferation under unstressed conditions (resulting in mutant clones consisting of mostly single SCs) (Biteau and Jasper, 2011Biteau B. Jasper H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila.Development. 2011; 138: 1045-1055Crossref PubMed Scopus (46) Google Scholar, Biteau et al., 2010Biteau B. Karpac J. Supoyo S. Degennaro M. Lehmann R. Jasper H. Lifespan extension by preserving proliferative homeostasis in Drosophila.PLoS Genet. 2010; 6: e1001159Crossref PubMed Scopus (44) Google Scholar, Jiang et al., 2011Jiang H. Grenley M.O. Bravo M.J. Blumhagen R.Z. Edgar B.A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila.Cell Stem Cell. 2011; 8: 84-95Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, Xu et al., 2011Xu N. Wang S.Q. Tan D. Gao Y. Lin G. Xi R. EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells.Dev. Biol. 2011; 354: 31-43Crossref PubMed Scopus (42) Google Scholar). Downstream mediators of these pathways include the InR Substrate, PI3Kinase, Akt, Ras, and ERK, and all of these molecules have also been shown to be essential for ISC proliferation. Consistent with a general permissive role for these signaling pathways, activated ERK (dpERK) can be detected in all ISCs under normal conditions (Biteau and Jasper, 2011Biteau B. Jasper H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila.Development. 2011; 138: 1045-1055Crossref PubMed Scopus (46) Google Scholar, Jiang et al., 2011Jiang H. Grenley M.O. Bravo M.J. Blumhagen R.Z. Edgar B.A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila.Cell Stem Cell. 2011; 8: 84-95Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, Xu et al., 2011Xu N. Wang S.Q. Tan D. Gao Y. Lin G. Xi R. EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells.Dev. Biol. 2011; 354: 31-43Crossref PubMed Scopus (42) Google Scholar). Interestingly, constitutive activation of EGFR/InR signaling components can also increase ISC proliferation rates, indicating that the level of RTK signaling activity modulates the proliferative state of ISCs (Biteau and Jasper, 2011Biteau B. Jasper H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila.Development. 2011; 138: 1045-1055Crossref PubMed Scopus (46) Google Scholar, Jiang et al., 2011Jiang H. Grenley M.O. Bravo M.J. Blumhagen R.Z. Edgar B.A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila.Cell Stem Cell. 2011; 8: 84-95Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, Xu et al., 2011Xu N. Wang S.Q. Tan D. Gao Y. Lin G. Xi R. EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells.Dev. Biol. 2011; 354: 31-43Crossref PubMed Scopus (42) Google Scholar). ISCs integrate local and systemic cues with cell-intrinsic signals to adapt their proliferation rate to tissue demand. Signaling pathways required for homeostatic proliferation are represented in green, and pathways required for stress- and injury-induced ISC proliferation are represented in red. In addition, the MAPK p38 is required for ISC proliferation under unstressed conditions (Park et al., 2009Park J.S. Kim Y.S. Yoo M.A. The role of p38b MAPK in age-related modulation of intestinal stem cell proliferation and differentiation in Drosophila.Aging (Albany NY). 2009; 1: 637-651PubMed Google Scholar), and it was suggested that it acts as a mediator of the effect of the PDGF/VEGF-like receptor signaling pathway (composed of Pvf ligands and the PvR receptor) on ISC proliferation (Choi et al., 2008Choi N.H. Kim J.G. Yang D.J. Kim Y.S. Yoo M.A. Age-related changes in Drosophila midgut are associated with PVF2, a PDGF/VEGF-like growth factor.Aging Cell. 2008; 7: 318-334Crossref PubMed Scopus (59) Google Scholar, Park et al., 2009Park J.S. Kim Y.S. Yoo M.A. The role of p38b MAPK in age-related modulation of intestinal stem cell proliferation and differentiation in Drosophila.Aging (Albany NY). 2009; 1: 637-651PubMed Google Scholar). It has not yet been established, however, whether Pvf and PvR are also required for homeostatic proliferation. Interestingly, ligands for the EGFR and the InR pathways are dynamically controlled in response to environmental challenges. Nutritional state can significantly affect insulin-like peptide (Dilp) expression, while oxidative stress or DNA damage results in repression of dilp expression (Géminard et al., 2009Géminard C. Rulifson E.J. Léopold P. Remote control of insulin secretion by fat cells in Drosophila.Cell Metab. 2009; 10: 199-207Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, Karpac et al., 2011Karpac J. Younger A. Jasper H. Dynamic coordination of innate immune signaling and insulin signaling regulates systemic responses to localized DNA damage.Dev. Cell. 2011; 20: 841-854Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, Slaidina et al., 2009Slaidina M. Delanoue R. Gronke S. Partridge L. Léopold P. A Drosophila insulin-like peptide promotes growth during nonfeeding states.Dev. Cell. 2009; 17: 874-884Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, Wang et al., 2005Wang M.C. Bohmann D. Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling.Cell. 2005; 121: 115-125Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). This regulation may thus allow the adjustment of ISC proliferation to systemic nutrient and stress levels (Amcheslavsky et al., 2009Amcheslavsky A. Jiang J. Ip Y.T. Tissue damage-induced intestinal stem cell division in Drosophila.Cell Stem Cell. 2009; 4: 49-61Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, McLeod et al., 2010McLeod C.J. Wang L. Wong C. Jones D.L. Stem cell dynamics in response to nutrient availability.Curr. Biol. 2010; 20: 2100-2105Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Nutrition also influences the activity of the TSC/Tor signaling pathway, and excessive Tor activation seems to have deleterious consequences for ISC activity (Amcheslavsky et al., 2011Amcheslavsky A. Ito N. Jiang J. Ip Y.T. Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells.J Cell Biol. 2011; 93: 695-710Crossref Scopus (18) Google Scholar). Infection with pathogenic bacteria, on the other hand, induces EGF-like ligand expression in the gut (Buchon et al., 2009bBuchon N. Broderick N.A. Poidevin M. Pradervand S. Lemaitre B. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation.Cell Host Microbe. 2009; 5: 200-211Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, Buchon et al., 2010Buchon N. Broderick N.A. Kuraishi T. Lemaitre B. Drosophila EGFR pathway coordinates stem cell proliferation and gut remodeling following infection.BMC Biol. 2010; 8: 152Crossref PubMed Scopus (56) Google Scholar, Jiang et al., 2011Jiang H. Grenley M.O. Bravo M.J. Blumhagen R.Z. Edgar B.A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila.Cell Stem Cell. 2011; 8: 84-95Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, Xu et al., 2011Xu N. Wang S.Q. Tan D. Gao Y. Lin G. Xi R. EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells.Dev. Biol. 2011; 354: 31-43Crossref PubMed Scopus (42) Google Scholar). These ligands are secreted by both epithelial cells (including ISCs and ECs), and the surrounding visceral muscle, displaying a remarkable redundancy and indicating that ISC maintenance and proliferation may be coordinated across the entire organ by ligands derived from multiple regions. Insulin and EGF-like growth factors thus serve as permissive signals for ISC proliferation, while also contributing to the proliferative response to stress. Recent studies in mammals support the idea that the mechanisms regulating SC proliferation in response to tissue injury are, at least partially, distinct from those essential for homeostatic regeneration. For example, the Hippo and Focal Adhesion Kinase pathways were recently shown to be required i" @default.
• W1989388426 created "2016-06-24" @default.
• W1989388426 creator A5063179526 @default.
• W1989388426 creator A5074287735 @default.
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• W1989388426 date "2011-11-01" @default.
• W1989388426 modified "2023-10-16" @default.
• W1989388426 title "Maintaining Tissue Homeostasis: Dynamic Control of Somatic Stem Cell Activity" @default.
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