Coordination of Growth and Cell Division in the Drosophila Wing

In most tissues, cell division is coordinated with increases in mass (i.e., growth). To understand this coordination, we altered rates of division in cell clones or compartments of the Drosophila wing and measured the effects on growth. Constitutive overproduction of the transcriptional regulator dE2F increased expression of the S- and M-phase initiators Cyclin E and String (Cdc25), thereby accelerating cell proliferation. Loss of dE2F or overproduction of its corepressor, RBF, retarded cell proliferation. These manipulations altered cell numbers over a 4- to 5-fold range but had little effect on clone or compartment sizes. Instead, changes in cell division rates were offset by changes in cell size. We infer that dE2F and RBF function specifically in cell cycle control, and that cell cycle acceleration is insufficient to stimulate growth. Variations in dE2F activity could be used to coordinate cell division with growth.

[1]  G. E. Marks.  The Giemsa-staining centromeres of Nigella damascena. , 1975, Journal of cell science.

[2]  M. Sheikh,et al.  Overexpression of p21WAF1/CIP1 induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines. , 1995, Oncogene.

[3]  S. Zipursky,et al.  Induction of Drosophila eye development by decapentaplegic. , 1997, Development.

[4]  J. Mitchison,et al.  The biology of the cell cycle , 1971 .

[5]  J. Nevins,et al.  Ectopic E2F expression induces S phase and apoptosis in Drosophila imaginal discs. , 1996, Genes & development.

[6]  A. Garcı́a-Bellido,et al.  Cell cycling and patterned cell proliferation in the Drosophila wing during metamorphosis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S. Saebøe-Larssen,et al.  A Drosophila third chromosome Minute locus encodes a ribosomal protein. , 1994, Genetics.

[8]  P. Miles.  Ferromagnetic Resonance in Ferrites , 1954, Nature.

[9]  G. Struhl,et al.  Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. , 1995, Development.

[10]  I. Royzman,et al.  Mutations in Drosophila DP and E2F distinguish G1-S progression from an associated transcriptional program. , 1997, Genes & development.

[11]  Marcos González-Gaitán,et al.  Cell proliferation patterns in the wing imaginal disc of Drosophila , 1994, Mechanisms of Development.

[12]  J. Nevins,et al.  Expression of transcription factor E2F1 induces quiescent cells to enter S phase , 1993, Nature.

[13]  Joseph R. Nevins,et al.  Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F , 1997, Nature.

[14]  S. Shurtleff,et al.  Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. , 1993, Genes & development.

[15]  R. Weinberg,et al.  Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts , 1996, Molecular and cellular biology.

[16]  P. O’Farrell,et al.  Genetic control of cell division patterns in the Drosophila embryo , 1989, Cell.

[17]  James M. Roberts,et al.  A Syndrome of Multiorgan Hyperplasia with Features of Gigantism, Tumorigenesis, and Female Sterility in p27 Kip1 -Deficient Mice , 1996, Cell.

[18]  Konrad Basler,et al.  Organizing activity of wingless protein in Drosophila , 1993, Cell.

[19]  J. Nevins,et al.  Functional properties of a Drosophila homolog of the E2F1 gene , 1994, Molecular and cellular biology.

[20]  G M Rubin,et al.  Expression of baculovirus P35 prevents cell death in Drosophila. , 1994, Development.

[21]  E. Hafen,et al.  The Drosophila phosphoinositide 3‐kinase Dp110 promotes cell growth. , 1996, The EMBO journal.

[22]  N. Dyson,et al.  Ectopic expression of dE2F and dDP induces cell proliferation and death in the Drosophila eye. , 1996, The EMBO journal.

[23]  N. Sonenberg,et al.  Eukaryotic Translation Initiation Factor 4E Regulates Expression of Cyclin D1 at Transcriptional and Post-transcriptional Levels (*) , 1995, The Journal of Biological Chemistry.

[24]  C. Lehner,et al.  Cell cycle progression, growth and patterning in imaginal discs despite inhibition of cell division after inactivation of Drosophila Cdc2 kinase. , 1997, Development.

[25]  P. O’Farrell,et al.  Limb morphogenesis: connections between patterning and growth , 1997, Current Biology.

[26]  P. O’Farrell,et al.  E2F-induced S phase requires cyclin E. , 1996, Genes & development.

[27]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[28]  S. Weintraub,et al.  Mechanism of active transcriptional repression by the retinoblastoma protein , 1995, Nature.

[29]  Edward T Kipreos,et al.  cul-1 Is Required for Cell Cycle Exit in C. elegans and Identifies a Novel Gene Family , 1996, Cell.

[30]  G. Rubin,et al.  Analysis of genetic mosaics in developing and adult Drosophila tissues. , 1993, Development.

[31]  A. Garcı́a-Bellido,et al.  Cell cycling and patterned cell proliferation in the wing primordium of Drosophila. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  G. Morata,et al.  Differential mitotic rates and patterns of growth in compartments in the Drosophila wing. , 1981, Developmental biology.

[33]  L. Taylor,et al.  Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product , 1995, Nature.

[34]  G. Schubiger,et al.  Cell cycle changes during growth and differentiation of imaginal leg discs in Drosophila melanogaster. , 1982, Developmental biology.

[35]  B. Edgar,et al.  Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing , 1998, Nature.

[36]  N. Dyson,et al.  DNA-binding and trans-activation properties of Drosophila E2F and DP proteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[37]  G. Grumbling,et al.  Vein is a novel component in the Drosophila epidermal growth factor receptor pathway with similarity to the neuregulins. , 1996, Genes & development.

[38]  M Lappé,et al.  Genetic control. , 1972, The New England journal of medicine.

[39]  B. Stevens,et al.  Alterations in the cell cycle of Drosophila imaginal disc cells precede metamorphosis. , 1982, Developmental biology.

[40]  B. Edgar,et al.  Developmental Control of Cell Cycle Regulators: A Fly's Perspective , 1996, Science.

[41]  M. Ewen,et al.  Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein , 1997, Nature.

[42]  R. Brent,et al.  Isolation of Drosophila cyclin D, a protein expressed in the morphogenetic furrow before entry into S phase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  G C Johnston,et al.  Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. , 1977, Experimental cell research.

[44]  M. Gossen,et al.  Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. , 1994, Molecular and cellular biology.

[45]  L. Hartwell,et al.  Genetic control of the cell division cycle in yeast. II. Genes controlling DNA replication and its initiation. , 1971, Journal of molecular biology.

[46]  E. Hafen,et al.  The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development. , 1994, Development.

[47]  M. Ewen,et al.  Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein , 1997, Nature.

[48]  D. Inzé,et al.  Dominant negative mutants of the Cdc2 kinase uncouple cell division from iterative plant development. , 1995, The EMBO journal.

[49]  P. Bryant,et al.  Drosophila in cancer research: the first fifty tumor suppressor genes , 1994, Journal of Cell Science.

[50]  Y. Jan,et al.  Delta is a ventral to dorsal signal complementary to Serrate, another Notch ligand, in Drosophila wing formation. , 1996, Genes & development.

[51]  S. Cohen,et al.  Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing , 1996, Nature.

[52]  A. Garcı́a-Bellido,et al.  Developmental parameters of cell death in the wing disc of Drosophila. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[53]  P. Bryant.  Cell proliferation control in Drosophila: flies are not worms. , 1996, BioEssays : news and reviews in molecular, cellular and developmental biology.

[54]  M. Vidal,et al.  RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. , 1996, Genes & development.

[55]  G. Morata,et al.  Developmental compartmentalisation of the wing disk of Drosophila. , 1973, Nature: New biology.

[56]  K. Basler,et al.  Dpp receptors are autonomously required for cell proliferation in the entire developing Drosophila wing. , 1996, Development.

[57]  S. Jackson,et al.  Repression of RNA polymerase III transcription by the retinoblastoma protein , 1996, Nature.

[58]  James M. Roberts,et al.  Cyclin-dependent regulation of G1 in mammalian fibroblasts. , 1993, Science.

[59]  L. Hartwell,et al.  Genetic control of the cell division cycle in yeast. , 1974, Science.

[60]  N. Dyson,et al.  Requirements for dE2F function in proliferating cells and in post‐mitotic differentiating cells. , 1996, The EMBO journal.

[61]  M. Polymenis,et al.  Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast. , 1997, Genes & development.

[62]  J. Shay,et al.  Involvement of pRB family in TGF beta-dependent epithelial cell hypertrophy , 1995, The Journal of cell biology.

[63]  P. O’Farrell,et al.  Developmental control of the G1 to S transition in Drosophila: cyclin Eis a limiting downstream target of E2F. , 1995, Genes & development.

[64]  G M Rubin,et al.  Ectopic expression of activated Ras1 induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. , 1998, Development.

[65]  I. Stansfield,et al.  An MBoC Favorite: TOR controls translation initiation and early G1 progression in yeast , 2012, Molecular biology of the cell.

[66]  A. Garcı́a-Bellido,et al.  Parameters of the wing imaginal disc development of Drosophila melanogaster. , 1971, Developmental biology.

[67]  G. Cooper,et al.  Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1 , 1997, Molecular and cellular biology.

[68]  P. O’Farrell,et al.  Mutations of the Drosophila dDP,dE2F, and cyclin E Genes Reveal Distinct Roles for the E2F-DP Transcription Factor and Cyclin E during the G1-S Transition , 1998, Molecular and Cellular Biology.

[69]  P. Simpson.  Parameters of cell competition in the compartments of the wing disc of Drosophila. , 1979, Developmental biology.

[70]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[71]  L. Hartwell,et al.  Genetic control of the cell division cycle in yeast. 3. Seven genes controlling nuclear division. , 1971, Experimental cell research.