Bruce A. Edgar

Bruce A. Edgar, PhD

Languages spoken: English

Academic Information

Departments Primary - Oncological Sciences , Adjunct - Human Genetics

Lab

Bruce Edgar (b1960) received a B.A. from Swarthmore College (1982), and a PhD in Genetics from the University of Washington (1987), where he studied with Gerold Schubiger. Dr. Edgar did postdoctoral work at UCSF and Oxford with Pat O’Farrell and Paul Nurse, respectively, and in 1993 started as an independent investigator at the Fred Hutchinson Cancer Research Center in Seattle.

From 2009-2016 he worked in Heidelberg, Germany, as a professor in the Center for Molecular Biology (ZMBH) and a division leader at the German Cancer Research Center (DKFZ). In 2016 Dr. Edgar moved his laboratory to the Huntsman Cancer Institute of the University of Utah. Since ~1986 Dr. Edgar’s research has used the Drosophila model system to study the control of cell growth and proliferation during development, tissue maintenance and tumorigenesis. A number of key cell cycle and growth regulatory genes have been identified and characterized, some of which play important roles in human disease, most notably cancer.

Current studies in Dr. Edgar’s lab focus on how the fly’s intestinal stem cells support regenerative growth, and how these stem cells can become tumorigenic.

Research Statement

Our Research

Our research focuses on the mechanisms that control cell growth and proliferation in the fruit fly, Drosophila melanogaster. The superlative genetic tools and fast life cycle of this tiny model organism make it a powerful system for discovery-based research, and its genetic similarity to humans makes much of what is discovered relevant to human biology and health. In the Edgar lab we use genetics to characterize the programs of cell growth and proliferation that occur during development, regeneration and tumorigenesis, with the goal of finding the genes that act as limiting regulators in each context. We furthermore seek to understand how networks of genes and communities of cells in a tissue function as integrated systems. Techniques in use in the lab range from classical and molecular genetics, to high resolution imaging, to whole genome gene expression profiling and RNAi screening.

Current projects in the lab fall in two areas. One set of projects focuses on the mechanisms of epithelial self-renewal in the intestine of the adult fly. A second set of projects addresses how G1/S progression – the initiation of DNA replication – is controlled by rates of cell growth and growth factor signaling. For both projects to overeaching goal is to define new mechanisms involved in growth control that are relevant to basic paradigms in cell and developmental biology, and to issues in human health such as cancer diagnosis and therapy, chronic inflammation, and regenerative medicine.

Epithelial renewal in the Drosophila intestine

Objective: To understand how cell-cell interactions, diet, the microbiota, and infection regulate the proliferation of intestinal stem cells, facilitating tissue self-renewal in healthy animals and, in tumor models, a loss of growth control.

Overview: Like mammals, insects have intestinal stem cells (ISCs) that drive dynamic self-renewal of the gut epithelium. The simplicity of the Drosophila midgut and the superior genetic tools available make this an attractive model for studies of stem cell biology and gut homeostasis. Cellular and molecular similarities to the human gut suggest relevance to diseases like colorectal cancer and inflammatory bowel disease. In exploring how ISC division is controlled, we discovered that damage to the intestinal epithelium results in a burst of stem cell division that facilitates rapid regeneration. To understand this regenerative response we have analyzed the functions of most of the major signaling pathways in each of the five intestinal cell types. We discovered that gut epithelial stress or damage induces JNK and p38-Map Kinase activity and suppresses Hippo signaling in epithelial enterocytes (ECs), and that this triggers the production of secreted cytokines (upd2, upd3) and EGFR ligands (Vn, Spi, Krn) that stimulate JAK/STAT and Ras/MAPK activity in the intestinal stem cells, activating them to grow and divide.

Approach: Our elucidation of a feedback system explaining gut homeostasis highlights new areas of research that can enhance our understanding of tissue biology and human disease. These include: how damage is sensed by the gut epithelium, how stress signaling activates growth factor and cytokine signaling and inflammation, how growth factor signaling activates stem cells, and how transformed stem cells develop into tumors and subvert the mechanisms that mediate normal gut homeostasis. Our understanding of the intestinal stem cell niche, how stem cell pools are controlled, and how differentiation is coordinated with ISC division is also incomplete. Classic questions in cell biology, such as how growth factor signaling activates cell growth and the cell cycle machinery, also remain insufficiently answered, and ripe for study in this system. Projects addressing each of these questions are currently underway in the lab.

Ongoing Research

1: How is gut epithelial damage sensed? When gut enterocytes (EC) are damaged or lost, the surrounding epithelium responds by producing IL-6- Leptin-like cytokines (Upd2, Upd2), which trigger a signaling cascade that activates ISCs to grow, divide, and produce new ECs. Our understanding of this damage response is so rudimentary that we don’t even know if the intial signals are chemical or mechanical. To identify the genes and pathways the gut uses to sense damage and trigger Upd3 expression, we are testing candidate pathways (Jnk, p38, Hpo) and processes (Ca++, ROS signaling), and performing a genome-scale RNAi screen. Genes found to be essential for damage sensing will be characterized and assigned to regulatory pathways. The results should yield general insight into how epithelial integrity is maintained, and how dysfuntion in damage sensing systems contributes to losses in epithelial homeostasis that lead to diseases like chronic inflammation and cancer.

2: How does EGFR signaling activate ISC proliferation? Signaling via the epidermal growth factor receptor (EGFR), Ras, and the mitogen activated protein kinase (MapK) is required and sufficient for ISC activation downstream of gut epithelial damage. Although intensively studied and central to an overwhelming number of cancers, how Ras/Mapk signaling actually drives cell growth and division is surprisingly poorly understood. We recently identified the transcriptional repressor Capicua (Cic) and two of its targets, the ETS transcription factors Pnt and Ets21C, as critical Ras-dependent effectors of ISC activation. Each of these genes is associated with human cancer, most likely as effectors of the Ras oncogene. Our current studies combine target gene identification with functional tests to determine the mechanisms by which these transcription factors activate ISC growth and division. We are also testing whether there are Cic- and ETS-independent functions of MapK signaling, and if there are, we will undertake to identify the critical targets.

3: What niche and host factors support the growth of ISC-derived tumors? We developed a tumor model in which intestinal stem cells expressing a differentiation inhibitor (NotchRNAi) and an EGFR signaling activator (RasV12G, RafAct, Pnt, Ers21C, or CicRNAi) generate rapidly growing tumors that can be serially transplanted in flies. After transplantation these aggressive tumors grow rapidly in many parts of the fly, recruit trachea, and kill the host. A gene replacement strategy is being used to determine the functions required to allow niche-independent stem cell tumor growth. Using genetically modified hosts, are also testing the requirement from the host animal, checking processes such as cell adhesion, epithelial tension, oxygen supply, blood cells, and nutrition, in niche-independent tumor growth. An RNAseq screen will also be used to identify other potentially relevant host processes. We hope to determine the full catalog of factors and conditions required for transformed ISCs to grow outside the stem cell niche.

4: Can ISC proliferation and differentiation be recapitulated in vitro? The lack of long-term primary cell or organ culture remains a major limitation to Drosophila as a model system for research. We are attempting to develop primary culture of Drosophila intestinal stem cells (ISCs) by testing combinations of genetic manipulations and culture conditions. A protocol for culturing ISCs will allow many new approaches for studying stem cell biology. These include live analysis of cell proliferation, lineage asymmetry and differentiation, cell-based RNAi screening, and molecular techniques like RNAseq, ChIP, and protein mass spectrometry that work best with large numbers of synchronous homogeneous cells.

Growth-dependent control of the Cell Cycle

Objective: To understand how the initiation of DNA replication (G1/S transition) is coordinated with rates of cell growth and controlled by growth factor signaling.

Overview: In growing animal cells, rates of cell cycle progression are usually tightly coupled to rates of cell growth (mass accumulation), such that cells divide each time they double their mass. The growth of animal cells is limited by nutrition via TOR signaling, and also regulated by signaling through receptor tyrosine kinases, cytokine receptors, and G-protein coupled-receptors. Genes in all of these pathways are highly associated with cancer development, and can be targeted for cancer therapy. A central question in cell biology is how growth factor signaling via these conduits controls the cell cycle. Many studies, both classic ones using human cells and from our lab using the Drosophila system, indicate that growth-coupled cell cycle control is executed principally at G1àS rather than G2àM transitions. Studies with human cells have engendered a model, depicted in many textbooks, wherein growth factor signaling triggers phosphorylation cascades that lead to the transcriptional activation of genes encoding G1 Cyclin-dependent Kinase (Cdk) complexes, which in turn trigger DNA replication. However our studies in Drosophila, as well as many studies from mice and yeast, do not support central aspects of this model. Instead, we suggest an alternative mechanism wherein translational regulation of limiting cell cycle regulators determines rates of G1àS progression.

We have been researching this issue using endocycling cells of the Drosophila gut and salivary glands. Endocycles consist of DNA Synthesis (S) and Gap phases (G) without intervening Mitoses (M). In most endoreplicating cells nutrition-dependent Insulin/TOR signaling is the principle driver of cell growth and DNA replication, but other inputs such as EGFR/MAPK signaling can also have important growth promoting functions. In 2011 we reported that the fly’s endocycles employ a novel bi-phasic oscillator in which the transcription factor E2F1 promotes cyclin E (cycE) transcription, CycE/Cdk2 then triggers S-phase, and S-phase in turn causes the destruction of E2F1 by activating a DNA-replication specific ubiquitin ligase, CRL4cdt2. Strikingly, factors that alter protein synthetic rates such as nutrition, TOR or Ras activity regulate E2F protein levels and thereby make endocycle progression growth-dependent. Our tests indicated that E2F protein levels in this context are controlled translationally, suggesting that translational efficiency provides the “missing link” between cell growth and G1àS progression in Drosophila. Recent studies in our lab indicate that in another endoreplicating cell type, the midgut Enteroblast (EB), EGFR/Ras/MapK signaling drives endocycling, also via translational control of E2F1. Notably, the mechanism we propose need not be relevant only to endocycles, but potentially controls G0 and/or G1 length in proliferating diploid cells.

Approach: Our ongoing studies have two goals. First, we are testing our translational model for coupling cell growth to G1àS progression, using reporter mRNAs derived from E2F1 and alterations in signaling and nutrition to modulate translation. Our intention is to confirm the translational model, define the mRNA sequences that mediate translational efficiency, and determine how they do this. Second, we would like to know which elements of the endocycle mechanism we’ve elucidated in Drosophila are conserved in mammalian cell cycles and in G1àS control in general. To investigate the question of conservation we are assaying the periodicity of tagged human E2F proteins, and their dependence on CRL4Cdt2, in cultured human cells.

Ongoing Research:

1: Translational control of E2F1. To further validate our model for G1àS control, we are characterizing the serum- Ras-, and TOR-dependent translational control of a set of E2F 5’UTR reporters. If these tests show that E2F 5’ UTRs mediate E2F translation, we will create further 5’ UTR deletion constructs to fine-map the mRNA sequences responsible (these will be translation suppression sequences). Then, CRISPR technology will be used to mutate these regulatory sites in the E2F locus in cells and flies, and their cell cycle progression phenotypes will be assayed. We expect such mutants to have shortened G1 periods, and to show some degree of growth factor- and nutrition-independence for G1àS progression. Using the E2F 5’ UTR elements defined above, we will screen for upstream translational regulators.

2: How does EGFR/MAPK signaling drive cell growth? EGFR/RAS/MAPK signaling drives the growth of many types of animal cells, most notably cancer cells transformed by activated mutant forms of RAS, RAF, NF2, ErbB2, and EGFR. It’s amazing that we don’t understand how this signaling pathway drives cell growth, but it clearly does. In Drosophila, the most profound growth effects we’ve discovered are in the adult intestinal stem cells (ISCs), Enteroblasts and their progenitors, the larval “Adult Midgut Progenitor” cells (AMPs). We are taking a multi-faceted approach to determine how EGFR signaling makes these cells grow. Epistasis tests are being used to test candidate downstream effectors such as RSK, AKT, and TOR components, and transcriptome and proteome profiling is being performed to identify potential targets.

3: Translational control of mitotic cycles via E2F1. Although most of our work has focused on endocycling cells, we believe that the cell cycle ingrowing mitotic cells is also highly subject to translational control. To test this theory, we are evaluating Drosophila E2F1 as a growth sensor in two mitotic cell types: wing progenitors and intestinal stem cells. In these experiments we alter oncogenic growth signaling (Myc, PI3K, Ras, Tor, Hpo) and measure how this affects levels of E2F1 protein, mRNA, and rates of cell division. If the results support translational control, the specific mechanism will be sought using E2F1-UTR mutants and trans-acting factors identified as above. These experiments will provide examples of how a growth sensor regulates proliferation in stem and progenitor cells, further validating the mechanism’s relevance to development and human disease.

4: Do human cells use growth-sensing cell cycle regulators? Answering this question could revise a central, cancer-relevant paradigm in cell biology and present new strategies for cellular growth control. In this project we are using ribosome profiling of normal human epithelial cells (RPE-1) to identify growth factor-dependent, translationally regulated genes that potentially regulate the cell cycle. Candidate genes so defined will be functionally tested to determine whether they actually regulate cell proliferation. Using ribosome density maps, we will address specific mechanisms of translational control and how these interface with growth and growth factor signaling.

Education History

Undergraduate Swarthmore College
 BA
Doctoral Training University of Washington
 PhD

Selected Publications

Journal Article

  1. O'Keefe DD, Thomas S, Edgar BA, Buttitta L (2014). Temporal regulation of Dpp signaling output in the Drosophila wing. Dev Dyn, 243(6), 818-32.
  2. O'Keefe DD, Edgar BA, Saucedo LJ (2011). EndoGI modulates Notch signaling and axon guidance in Drosophila. Mech Dev, 128(1-2), 59-70.
  3. Campbell SD, Sprenger F, Edgar BA, O'Farrell PH (1995). Drosophila Wee1 kinase rescues fission yeast from mitotic catastrophe and phosphorylates Drosophila Cdc2 in vitro. Mol Biol Cell, 6(10), 1333-47.
  4. Migeon JC, Garfinkel MS, Edgar BA (1999). Cloning and characterization of peter pan, a novel Drosophila gene required for larval growth. Mol Biol Cell, 10(6), 1733-44.
  5. Zielke N, van Straaten M, Bohlen J, Edgar BA (2016). Using the Fly-FUCCI System for the Live Analysis of Cell Cycle Dynamics in Cultured Drosophila Cells. Methods Mol Biol, 1342, 305-20.
  6. Edgar BA, O'Farrell PH (1990). The three postblastoderm cell cycles of Drosophila embryogenesis are regulated in G2 by string. Cell, 62(3), 469-80.
  7. Edgar BA, Schubiger G (1986). Parameters controlling transcriptional activation during early Drosophila development. Cell, 44(6), 871-7.
  8. Edgar BA, O'Farrell PH (1989). Genetic control of cell division patterns in the Drosophila embryo. Cell, 57(1), 177-87.
  9. Edgar BA, Kiehle CP, Schubiger G (1986). Cell cycle control by the nucleo-cytoplasmic ratio in early Drosophila development. Cell, 44(2), 365-72.
  10. Edgar BA, Weir MP, Schubiger G, Kornberg T (1986). Repression and turnover pattern fushi tarazu RNA in the early Drosophila embryo. Cell, 47(5), 747-54.
  11. Payvar F, DeFranco D, Firestone GL, Edgar B, Wrange O, Okret S, Gustafsson JA, Yamamoto KR (1983). Sequence-specific binding of glucocorticoid receptor to MTV DNA at sites within and upstream of the transcribed region. Cell, 35(2 Pt 1), 381-92.
  12. Neufeld TP, de la Cruz AF, Johnston LA, Edgar BA (1998). Coordination of growth and cell division in the Drosophila wing. Cell, 93(7), 1183-93.
  13. Johnston LA, Prober DA, Edgar BA, Eisenman RN, Gallant P (1999). Drosophila myc regulates cellular growth during development. Cell, 98(6), 779-90.
  14. Prober DA, Edgar BA (2000). Ras1 promotes cellular growth in the Drosophila wing. Cell, 100(4), 435-46.
  15. Reis T, Edgar BA (2004). Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing. Cell, 117(2), 253-64.
  16. Jiang H, Patel PH, Kohlmaier A, Grenley MO, McEwen DG, Edgar BA (2009). Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell, 137(7), 1343-55.
  17. Edgar BA, Odell GM, Schubiger (1989). A genetic switch, based on negative regulation, sharpens stripes in Drosophila embryos. Developmental genetics, 10(3), 124-42.
  18. Orian A, Grewal SS, Knoepfler PS, Edgar BA, Parkhurst SM, Eisenman R (2005). Genomic binding and transcriptional regulation by the Drosophila Myc and Mnt transcription factors. Cold Spring Harbor symposia on quantitative biology, 70, 299-307.
  19. O'Keefe DD, Prober DA, Moyle PS, Rickoll WL, Edgar B (2007). Egfr/Ras signaling regulates DE-cadherin/Shotgun localization to control vein morphogenesis in the Drosophila wing. Developmental biology, 311(1), 25-39.
  20. O'Keefe DD, Gonzalez-Niño E, Burnett M, Dylla L, Lambeth SM, Licon E, Amesoli C, Edgar BA, Curtiss (2009). Rap1 maintains adhesion between cells to affect Egfr signaling and planar cell polarity in Drosophila. Developmental biology, 333(1), 143-60.
  21. O'Keefe DD, Gonzalez-Niño E, Edgar BA, Curtiss (2012). Discontinuities in Rap1 activity determine epithelial cell morphology within the developing wing of Drosophila. Developmental biology, 369(2), 223-34.
  22. Zhou J, Florescu S, Boettcher AL, Luo L, Dutta D, Kerr G, Cai Y, Edgar BA, Boutros (2015). Dpp/Gbb signaling is required for normal intestinal regeneration during infection. Developmental biology, 399(2), 189-203.
  23. Edgar BA, Lehman DA, O'Farrell P (1994). Transcriptional regulation of string (cdc25): a link between developmental programming and the cell cycle. Development (Cambridge, England), 120(11), 3131-43.
  24. Britton JS, Edgar B (1998). Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development (Cambridge, England), 125(11), 2149-58.
  25. Lehman DA, Patterson B, Johnston LA, Balzer T, Britton JS, Saint R, Edgar B (1999). Cis-regulatory elements of the mitotic regulator, string/Cdc25. Development (Cambridge, England), 126(9), 1793-803.
  26. Galloni M, Edgar B (1999). Cell-autonomous and non-autonomous growth-defective mutants of Drosophila melanogaster. Development (Cambridge, England), 126(11), 2365-75.
  27. Frank DJ, Edgar BA, Roth M (2002). The Drosophila melanogaster gene brain tumor negatively regulates cell growth and ribosomal RNA synthesis. Development (Cambridge, England), 129(2), 399-407.
  28. Martín-Castellanos C, Edgar B (2002). A characterization of the effects of Dpp signaling on cell growth and proliferation in the Drosophila wing. Development (Cambridge, England), 129(4), 1003-13.
  29. Pierce SB, Yost C, Britton JS, Loo LW, Flynn EM, Edgar BA, Eisenman R (2004). dMyc is required for larval growth and endoreplication in Drosophila. Development (Cambridge, England), 131(10), 2317-27.
  30. Jiang H, Edgar B (2009). EGFR signaling regulates the proliferation of Drosophila adult midgut progenitors. Development (Cambridge, England), 136(3), 483-93.
  31. Shaw RL, Kohlmaier A, Polesello C, Veelken C, Edgar BA, Tapon (2010). The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development (Cambridge, England), 137(24), 4147-58.
  32. Meyer CA, Jacobs HW, Datar SA, Du W, Edgar BA, Lehner C (2000). Drosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression. The EMBO journal, 19(17), 4533-42.
  33. Datar SA, Jacobs HW, de la Cruz AF, Lehner CF, Edgar B (2000). The Drosophila cyclin D-Cdk4 complex promotes cellular growth. The EMBO journal, 19(17), 4543-54.
  34. Frei C, Galloni M, Hafen E, Edgar B (2005). The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth. The EMBO journal, 24(3), 623-34.
  35. Korzelius J, Naumann SK, Loza-Coll MA, Chan JS, Dutta D, Oberheim J, Gläßer C, Southall TD, Brand AH, Jones DL, Edgar B (2014). Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells. The EMBO journal, 33(24), 2967-82.
  36. Oberacker T, Bajorat J, Ziola S, Schroeder A, Röth D, Kastl L, Edgar BA, Wagner W, Gülow K, Krammer P (2018). Enhanced expression of thioredoxin-interacting-protein regulates oxidative DNA damage and aging. FEBS letters, 592(13), 2297-2307.
  37. Weir MP, Edgar BA, Kornberg T, Schubiger (1988). Spatial regulation of engrailed expression in the Drosophila embryo. Genes & development, 2(9), 1194-203.
  38. Edgar BA, Odell GM, Schubiger (1987). Cytoarchitecture and the patterning of fushi tarazu expression in the Drosophila blastoderm. Genes & development, 1(10), 1226-37.
  39. Edgar BA, Sprenger F, Duronio RJ, Leopold P, O'Farrell P (1994). Distinct molecular mechanism regulate cell cycle timing at successive stages of Drosophila embryogenesis. Genes & development, 8(4), 440-52.
  40. Edgar BA, Datar S (1996). Zygotic degradation of two maternal Cdc25 mRNAs terminates Drosophila's early cell cycle program. Genes & development, 10(15), 1966-77.
  41. Prober DA, Edgar B (2002). Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing. Genes & development, 16(17), 2286-99.
  42. Orian A, van Steensel B, Delrow J, Bussemaker HJ, Li L, Sawado T, Williams E, Loo LW, Cowley SM, Yost C, Pierce S, Edgar BA, Parkhurst SM, Eisenman R (2003). Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes & development, 17(9), 1101-14.
  43. Emmerich J, Meyer CA, de la Cruz AF, Edgar BA, Lehner C (2004). Cyclin D does not provide essential Cdk4-independent functions in Drosophila. Genetics, 168(2), 867-75.
  44. Bajorat J, Oberacker T, Ziola S, Edgar BA, Gülow K, Krammer P (2014). AF-1 a novel regulator of the redox equilibrium during aging. Free radical biology & medicine, 75 Suppl 1, S22-3.
  45. Grewal SS, Evans JR, Edgar B (2007). Drosophila TIF-IA is required for ribosome synthesis and cell growth and is regulated by the TOR pathway. The Journal of cell biology, 179(6), 1105-13.
  46. Wang T, Lao U, Edgar B (2009). TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. The Journal of cell biology, 186(5), 703-11.
  47. Buttitta LA, Katzaroff AJ, Edgar B (2010). A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo. The Journal of cell biology, 189(6), 981-96.
  48. Shinedling S, Singer BS, Gayle M, Pribnow D, Jarvis E, Edgar B, Gold (1987). Sequences and studies of bacteriophage T4 rII mutants. Journal of molecular biology, 195(3), 471-80.
  49. Loo LW, Secombe J, Little JT, Carlos LS, Yost C, Cheng PF, Flynn EM, Edgar BA, Eisenman R (2005). The transcriptional repressor dMnt is a regulator of growth in Drosophila melanogaster. Molecular and cellular biology, 25(16), 7078-91.
  50. Wang T, Blumhagen R, Lao U, Kuo Y, Edgar B (2012). LST8 regulates cell growth via target-of-rapamycin complex 2 (TORC2). Molecular and cellular biology, 32(12), 2203-13.
  51. Johnston LA, Edgar B (1998). Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature, 394(6688), 82-4.
  52. Zielke N, Kim KJ, Tran V, Shibutani ST, Bravo MJ, Nagarajan S, van Straaten M, Woods B, von Dassow G, Rottig C, Lehner CF, Grewal SS, Duronio RJ, Edgar B (2011). Control of Drosophila endocycles by E2F and CRL4(CDT2). Nature, 480(7375), 123-7.
  53. Moreno S, Edgar BA, Nurse (1994). Regulation of progression through the G1 phase of the cell cycle by the rum1+ gene. Nature, 367, 236-42.
  54. Song M, Zhang Y, Katzaroff AJ, Edgar BA, Buttitta (2014). Hunting complex differential gene interaction patterns across molecular contexts. Nucleic acids research, 42(7), e57.
  55. Kohlmaier A, Fassnacht C, Jin Y, Reuter H, Begum J, Dutta D, Edgar B (2015). Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine. Oncogene, 34(18), 2371-84.
  56. Edwards KA, Montague RA, Shepard S, Edgar BA, Erikson RL, Kiehart D (1994). Identification of Drosophila cytoskeletal proteins by induction of abnormal cell shape in fission yeast. Proceedings of the National Academy of Sciences of the United States of America, 91(10), 4589-93.
  57. Strilbytska OM, Semaniuk UV, Storey KB, Edgar BA, Lushchak O (2017). Activation of the Tor/Myc signaling axis in intestinal stem and progenitor cells affects longevity, stress resistance and metabolism in drosophila. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology, 203, 92-99.
  58. Oren-Giladi P, Krieger O, Edgar BA, Chamovitz DA, Segal (2008). Cop9 signalosome subunit 8 (CSN8) is essential for Drosophila development. Genes to cells, 13(3), 221-31.
  59. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar B (2003). Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature cell biology, 5(6), 566-71.
  60. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan (2003). Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature cell biology, 5(6), 578-81.
  61. Grewal SS, Li L, Orian A, Eisenman RN, Edgar B (2005). Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nature cell biology, 7(3), 295-302.
  62. Patel PH, Dutta D, Edgar B (2015). Niche appropriation by Drosophila intestinal stem cell tumours. Nature cell biology, 17(9), 1182-92.
  63. O'Keefe DD, Thomas SR, Bolin K, Griggs E, Edgar BA, Buttitta L (2012). Combinatorial control of temporal gene expression in the Drosophila wing by enhancers and core promoters. BMC genomics, 13, 498.
  64. Li L, Edgar BA, Grewal S (2010). Nutritional control of gene expression in Drosophila larvae via TOR, Myc and a novel cis-regulatory element. BMC cell biology, 11, 7.
  65. Doumpas N, Ruiz-Romero M, Blanco E, Edgar B, Corominas M, Teleman A (2013). Brk regulates wing disc growth in part via repression of Myc expression. EMBO reports, 14(3), 261-8.
  66. Britton JS, Lockwood WK, Li L, Cohen SM, Edgar B (2002). Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Developmental cell, 2(2), 239-49.
  67. Frei C, Edgar B (2004). Drosophila cyclin D/Cdk4 requires Hif-1 prolyl hydroxylase to drive cell growth. Developmental cell, 6(2), 241-51.
  68. Buttitta LA, Katzaroff AJ, Perez CL, de la Cruz A, Edgar B (2007). A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila. Developmental cell, 12(4), 631-43.
  69. Shibutani ST, de la Cruz AF, Tran V, Turbyfill WJ 3rd, Reis T, Edgar BA, Duronio R (2008). Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase. Developmental cell, 15(6), 890-900.
  70. Zhang P, Pei C, Wang X, Xiang J, Sun BF, Cheng Y, Qi X, Marchetti M, Xu JW, Sun YP, Edgar BA, Yuan (2017). A Balance of Yki/Sd Activator and E2F1/Sd Repressor Complexes Controls Cell Survival and Affects Organ Size. Developmental cell, 43(5), 603-617.e5.
  71. Zhang P, Holowatyj AN, Roy T, Pronovost SM, Marchetti M, Liu H, Ulrich CM, Edgar B (2019). An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling. Developmental cell, 49(4), 574-589.e5.
  72. Datar SA, Galloni M, de la Cruz A, Marti M, Edgar BA, Frei (2006). Mammalian cyclin D1/Cdk4 complexes induce cell growth in Drosophila. Cell cycle (Georgetown, Tex.), 5(6), 647-52.
  73. Icreverzi A, de la Cruz AF, Van Voorhies WA, Edgar B (2012). Drosophila cyclin D/Cdk4 regulates mitochondrial biogenesis and aging and sensitizes animals to hypoxic stress. Cell cycle (Georgetown, Tex.), 11(3), 554-68.
  74. Icreverzi A, de la Cruz AF, Walker DW, Edgar B (2015). Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress. Aging cell, 14(5), 896-906.
  75. Icreverzi, A., de la Cruz, AFA., Edgar, B (2015). Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress. Aging cell, 14(5), 896-906.
  76. Hall DJ, Grewal SS, de la Cruz AF, Edgar B (2007). Rheb-TOR signaling promotes protein synthesis, but not glucose or amino acid import, in Drosophila. BMC biology, 5, 10.
  77. Bandura JL, Jiang H, Nickerson DW, Edgar B (2013). The molecular chaperone Hsp90 is required for cell cycle exit in Drosophila melanogaster. PLoS genetics, 9(9), e1003835.
  78. Jin Y, Ha N, Forés M, Xiang J, Gläßer C, Maldera J, Jiménez G, Edgar B (2015). EGFR/Ras Signaling Controls Drosophila Intestinal Stem Cell Proliferation via Capicua-Regulated Genes. PLoS genetics, 11(12), e1005634.
  79. Oron E, Tuller T, Li L, Rozovsky N, Yekutieli D, Rencus-Lazar S, Segal D, Chor B, Edgar BA, Chamovitz D (2007). Genomic analysis of COP9 signalosome function in Drosophila melanogaster reveals a role in temporal regulation of gene expression. Molecular systems biology, 3, 108.
  80. Brown HL, Kaun KR, Edgar B (2012). The small GTPase Rheb affects central brain neuronal morphology and memory formation in Drosophila. PloS one, 7(9), e44888.
  81. Jiang H, Grenley MO, Bravo MJ, Blumhagen RZ, Edgar B (2011). EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell stem cell, 8(1), 84-95.
  82. Dutta D, Xiang J, Edgar B (2013). RNA expression profiling from FACS-isolated cells of the Drosophila intestine. Current protocols in stem cell biology, 27, Unit 2F.2..
  83. Dutta D, Buchon N, Xiang J, Edgar B (2015). Regional Cell Specific RNA Expression Profiling of FACS Isolated Drosophila Intestinal Cell Populations. Current protocols in stem cell biology, 34, 2F.2.1-14.
  84. Zhou J, Edgar BA, Boutros (2017). ATF3 acts as a rheostat to control JNK signalling during intestinal regeneration. Nature communications, 8, 14289.
  85. Xiang J, Bandura J, Zhang P, Jin Y, Reuter H, Edgar B (2017). EGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration. Nature communications, 8, 15125.
  86. Kuo Y, Ren S, Lao U, Edgar BA, Wang (2013). Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110. Cell death & disease, 4, e833.
  87. Joe Song M, Hong CC, Zhang Y, Buttitta L, Edgar B (2009). Comparative Generalized Logic Modeling Reveals Differential Gene Interactions during Cell Cycle Exit in Drosophila Wing Development. GI-Edition. Proceedings, 157, 143-152.
  88. Zielke N, Korzelius J, van Straaten M, Bender K, Schuhknecht GFP, Dutta D, Xiang J, Edgar B (2014). Fly-FUCCI: A versatile tool for studying cell proliferation in complex tissues. Cell reports, 7(2), 588-598.
  89. Dutta D, Dobson AJ, Houtz PL, Gläßer C, Revah J, Korzelius J, Patel PH, Edgar BA, Buchon (2015). Regional Cell-Specific Transcriptome Mapping Reveals Regulatory Complexity in the Adult Drosophila Midgut. Cell reports, 12(2), 346-58.
  90. García Del Arco A, Edgar BA, Erhardt (2018). In Vivo Analysis of Centromeric Proteins Reveals a Stem Cell-Specific Asymmetry and an Essential Role in Differentiated, Non-proliferating Cells. Cell reports, 22(8), 1982-1993.
  91. Jin Y, Patel PH, Kohlmaier A, Pavlovic B, Zhang C, Edgar B (2017). Intestinal Stem Cell Pool Regulation in Drosophila. Stem cell reports, 8(6), 1479-1487.
  92. Øvrebø JI, Bradley-Gill MR, Zielke N, Kim M, Marchetti M, Bohlen J, Lewis M, van Straaten M, Moon NS, Edgar B (2022). Translational control of E2f1 regulates the Drosophila cell cycle. Proceedings of the National Academy of Sciences of the United States of America, 119(4),
  93. Tamamouna V, Rahman MM, Petersson M, Charalambous I, Kux K, Mainor H, Bolender V, Isbilir B, Edgar BA, Pitsouli (2021). Remodelling of oxygen-transporting tracheoles drives intestinal regeneration and tumorigenesis in Drosophila. Nature cell biology, 23(5), 497-510.
  94. Tauc HM, Rodriguez-Fernandez IA, Hackney JA, Pawlak M, Ronnen Oron T, Korzelius J, Moussa HF, Chaudhuri S, Modrusan Z, Edgar BA, Jasper (2021). Age-related changes in polycomb gene regulation disrupt lineage fidelity in intestinal stem cells. eLife, 10,
  95. Ahmed SMH, Maldera JA, Krunic D, Paiva-Silva GO, Pénalva C, Teleman AA, Edgar B (2020). Fitness trade-offs incurred by ovary-to-gut steroid signalling in Drosophila. Nature, 584(7821), 415-419.
  96. Kwon YV, Zhao B, Xu C, Lee J, Chen CL, Vinayagam A, Edgar BA, Perrimon (2019). The role of translationally controlled tumor protein in proliferation of Drosophila intestinal stem cells. Proceedings of the National Academy of Sciences of the United States of America, 116, 26591-26598.
  97. Patel PH, Pénalva C, Kardorff M, Roca M, Pavlovi¿ B, Thiel A, Teleman AA, Edgar B (2019). Damage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut. Nature communications, 10(1), 4365.
  98. Zhang P, Katzaroff AJ, Buttitta LA, Ma Y, Jiang H, Nickerson DW, Øvrebø JI, Edgar B (2021). The Krüppel-like factor Cabut has cell cycle regulatory properties similar to E2F1. Proceedings of the National Academy of Sciences of the United States of America, 118(7),
  99. Zhang C, Jin Y, Marchetti M, Lewis MR, Hammouda OT, Edgar B (2022). EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and ß-oxidation. Current biology, 32, 3704-3719.e7.
  100. Marchetti M, Zhang C, Edgar B (2022). An improved organ explant culture method reveals stem cell lineage dynamics in the adult Drosophila intestine. eLife, 11,
  101. Puig-Barbe A, Dettmann S, Nirello VD, Moor H, Azami S, Edgar BA, Varga-Weisz P, Korzelius J, de Navascués (2025). A bHLH interaction code controls bipotential differentiation and self-renewal in the Drosophila gut. Cell reports, 44(3), 115398.

Review

  1. Edgar B (1995). Diversification of cell cycle controls in developing embryos. [Review]. Curr Opin Cell Biol, 7, (6), 815-24.
  2. Neufeld TP, Edgar BA (1998). Connections between growth and the cell cycle. [Review]. Curr Opin Cell Biol, 10, (6), 784-90.
  3. Buttitta LA, Edgar BA (2007). Mechanisms controlling cell cycle exit upon terminal differentiation. [Review]. Curr Opin Cell Biol, 19, (6), 697-704.
  4. Kohlmaier A, Edgar BA (2008). Proliferative control in Drosophila stem cells. [Review]. Curr Opin Cell Biol, 20, (6), 699-706.
  5. Prober DA, Edgar BA (2001). Growth regulation by oncogenes--new insights from model organisms. [Review]. Curr Opin Genet Dev, 11, (1), 19-26.
  6. Saucedo LJ, Edgar BA (2002). Why size matters: altering cell size. [Review]. Curr Opin Genet Dev, 12, (5), 565-71.
  7. Jiang H, Edgar BA (2012). Intestinal stem cell function in Drosophila and mice. [Review]. Curr Opin Genet Dev, 22, (4), 354-60.
  8. Edgar BA (2006). From cell structure to transcription: Hippo forges a new path. [Review]. Cell, 124, (2), 267-73.
  9. Edgar BA, Orr-Weaver T (2001). Endoreplication cell cycles: more for less. Cell, 105(3), 297-306.
  10. Ovrebo JI, Edgar B (2018). Polyploidy in tissue homeostasis and regeneration.LID - dev156034 [pii]LID - 10.1242/dev.156034 [doi]. Development (Cambridge, England), 145(14),
  11. Jiang H, Edgar B (2011). Intestinal stem cells in the adult Drosophila midgut. Experimental cell research, 317(19), 2780-8.
  12. O'Farrell PH, Edgar BA, Lakich D, Lehner C (1989). Directing cell division during development. Science (New York, N.Y.), 246(4930), 635-40.
  13. Edgar BA, Lehner C (1996). Developmental control of cell cycle regulators: a fly's perspective. Science (New York, N.Y.), 274(5293), 1646-52.
  14. Edgar B (1994). Cell cycle. Cell-cycle control in a developmental context. Current biology, 4(6), 522-4.
  15. Edgar B (1999). From small flies come big discoveries about size control. Nature cell biology, 1(8), E191-3.
  16. Buttitta LA, Edgar B (2007). How size is controlled: from Hippos to Yorkies. Nature cell biology, 9(11), 1225-7.
  17. Edgar B (2006). How flies get their size: genetics meets physiology. Nature reviews. Genetics, 7(12), 907-16.
  18. Saucedo LJ, Edgar B (2007). Filling out the Hippo pathway. Nature reviews. Molecular cell biology, 8(8), 613-21.
  19. Edgar BA, Zielke N, Gutierrez (2014). Endocycles: a recurrent evolutionary innovation for post-mitotic cell growth. Nature reviews. Molecular cell biology, 15(3), 197-210.
  20. Grewal SS, Edgar B (2003). Controlling cell division in yeast and animals: does size matter?. Journal of biology, 2(1), 5.
  21. Øvrebø JI, Ma Y, Edgar B (2022). Cell growth and the cell cycle: New insights about persistent questions. BioEssays, 44(11), e2200150.

Book Chapter

  1. de la Cruz AF, Edgar BA (2008). Flow cytometric analysis of Drosophila cells. In Methods Mol Biol (420, pp. 373-89). United States.
  2. Schubiger G, Edgar (1994). Using inhibitors to study embryogenesis. Methods in cell biology, 44, 697-713.
  3. Edgar BA, Britton J, de la Cruz AF, Johnston LA, Lehman D, Martin-Castellanos C, Prober (2001). Pattern- and growth-linked cell cycles in Drosophila development. Novartis Foundation symposium, 237, 3-12; discussion 12-8, 36-42.
  4. Zielke N, Edgar BA, DePamphilis M (2013). Endoreplication. Cold Spring Harbor perspectives in biology, 5(1), a012948.
  5. Wang T, Edgar B (2010). TOR signaling and cell death. 28, 217-44.
  6. Edgar B, Nijhout H (2004). Growth and Cell Cycle Control in Drosophila. 23-83.
  7. Foe VE, Odell GM, Edgar B (1993). Mitosis and morphogenesis in the Drosophila embryo: Point and counterpoint. 149-300.
  8. Zhang P, Edgar B (2022). Insect Gut Regeneration. Cold Spring Harbor perspectives in biology, 14(2),

Commentary

  1. Edgar B (2012). Intestinal stem cells: no longer immortal but ever so clever.... The EMBO journal, 31(11), 2441-3.
  2. Patel PH, Maldera JA, Edgar B (2013). Stimulating cROSstalk between commensal bacteria and intestinal stem cells. The EMBO journal, 32(23), 3009-10.
  3. Edgar BA, Grewal S (2017). Longer life through an odd Pol enzyme. Nature, 552(7684), 182-183.
  4. Edgar BA, Kim K (2009). Cell biology. Sizing up the cell. Science (New York, N.Y.), 325(5937), 158-9.
  5. Patel PH, Edgar B (2014). Tissue design: how Drosophila tumors remodel their neighborhood. Seminars in cell & developmental biology, 28, 86-95.
  6. Bandura JL, Edgar B (2008). Yorkie and Scalloped: partners in growth activation. Developmental cell, 14(3), 315-6.
  7. Zhang P, Holowatyj AN, Ulrich CM, Edgar B (2019). Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis. Autophagy, 15(9), 1668-1670.
  8. Zielke N, Edgar B (2015). FUCCI sensors: powerful new tools for analysis of cell proliferation. Wiley interdisciplinary reviews. Developmental biology, 4(5), 469-87.
  9. Knop M, Edgar B (2014). Tracking protein turnover and degradation by microscopy: photo-switchable versus time-encoded fluorescent proteins. Open biology, 4, 140002.
  10. Ma Y, Edgar B (2021). CDK4: Linking cell size to cell cycle control. Developmental cell, 56(12), 1695-1696.
  11. Zhang P, Edgar B (2020). Lipoic acid and autophagy: new insights into stem cell aging. EMBO reports, 21(8), e51175.

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