Advances in in vivo bioluminescence imaging of gene expression.

To advance our understanding of biological processes as they occur in living animals, imaging strategies have been developed and refined that reveal cellular and molecular features of biology and disease in real time. One rapid and accessible technology for in vivo analysis employs internal biological sources of light emitted from luminescent enzymes, luciferases, to label genes and cells. Combining this reporter system with the new generation of charge coupled device (CCD) cameras that detect the light transmitted through the animal's tissues has opened the door to sensitive in vivo measurements of mammalian gene expression in living animals. Here, we review the development and application of this imaging strategy, in vivo bioluminescence imaging (BLI), together with in vivo fluorescence imaging methods, which has enabled the real-time study of immune cell trafficking, of various genetic regulatory elements in transgenic mice, and of in vivo gene transfer. BLI has been combined with fluorescence methods that together offer access to in vivo measurements that were not previously available. Such studies will greatly facilitate the functional analysis of a wide range of genes for their roles in health and disease.

[1]  M. J. Cormier,et al.  Purification and properties of Renilla reniformis luciferase. , 1977, Biochemistry.

[2]  C. Nüsslein-Volhard,et al.  Mutations affecting segment number and polarity in Drosophila , 1980, Nature.

[3]  W D McElroy,et al.  Firefly and bacterial luminescence: basic science and applications. , 1983, Journal of applied biochemistry.

[4]  K. Wood,et al.  Cloning of firefly luciferase cDNA and the expression of active luciferase in Escherichia coli. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[5]  K. Wood,et al.  Firefly luciferase gene: structure and expression in mammalian cells , 1987, Molecular and cellular biology.

[6]  G P Nolan,et al.  Fluorescence-activated cell analysis and sorting of viable mammalian cells based on beta-D-galactosidase activity after transduction of Escherichia coli lacZ. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[7]  W D McElroy,et al.  Complementary DNA coding click beetle luciferases can elicit bioluminescence of different colors. , 1989, Science.

[8]  S. Benzer,et al.  Targeted gene mutations in Drosophila. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P. Leder,et al.  The cytomegalovirus enhancer: a pan-active control element in transgenic mice , 1990, Molecular and cellular biology.

[10]  C E Hooper,et al.  CCD imaging of luciferase gene expression in single mammalian cells. , 1990, Journal of bioluminescence and chemiluminescence.

[11]  J. Kondo,et al.  Structure and regulation of rat long-chain acyl-CoA synthetase. , 1990, The Journal of biological chemistry.

[12]  G. Winter,et al.  Phage antibodies: filamentous phage displaying antibody variable domains , 1990, Nature.

[13]  K. Nealson,et al.  Cloning, organization, and expression of the bioluminescence genes of Xenorhabdus luminescens , 1990, Journal of bacteriology.

[14]  K. Wood,et al.  Luc genes: introduction of colour into bioluminescence assays. , 1990, Journal of bioluminescence and chemiluminescence.

[15]  A. Welch,et al.  A review of the optical properties of biological tissues , 1990 .

[16]  G. Nolan,et al.  Improved FACS-Gal: flow cytometric analysis and sorting of viable eukaryotic cells expressing reporter gene constructs. , 1991, Cytometry.

[17]  K Nakatsu,et al.  Does carbon monoxide have a physiological function? , 1991, Trends in pharmacological sciences.

[18]  E. Meighen,et al.  Molecular biology of bacterial bioluminescence. , 1991, Microbiological reviews.

[19]  N Kajiyama,et al.  Isolation and characterization of mutants of firefly luciferase which produce different colors of light. , 1991, Protein engineering.

[20]  M. J. Cormier,et al.  Isolation and expression of a cDNA encoding Renilla reniformis luciferase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Ron,et al.  Luciferase reporter gene assay in mammalian cells. , 1992, Methods in enzymology.

[22]  M. P. Gallagher,et al.  Light emission from a Mudlux transcriptional fusion in Salmonella typhimurium is stimulated by hydrogen peroxide and by interaction with the mouse macrophage cell line J774.2 , 1993, Infection and immunity.

[23]  E. Meighen,et al.  Bacterial bioluminescence: organization, regulation, and application of the lux genes , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  K. Wood,et al.  Firefly Luciferase Engineered for Improved Genetic Reporting , 1994 .

[25]  M. Chalfie,et al.  Green fluorescent protein as a marker for gene expression. , 1994, Science.

[26]  J. Mullins,et al.  Photonic detection of bacterial pathogens in living hosts , 1995, Molecular microbiology.

[27]  A A Szalay,et al.  Monitoring of spatial expression of firefly luciferase in transformed zebrafish. , 1995, Journal of bioluminescence and chemiluminescence.

[28]  G. Rutter,et al.  Involvement of MAP kinase in insulin signalling revealed by non-invasive imaging of luciferase gene expression in single living cells , 1995, Current Biology.

[29]  B. Seed.  Developments in expression cloning. , 1995, Current opinion in biotechnology.

[30]  M. Braddock,et al.  Real-time analysis of the transcriptional regulation of HIV and hCMV promoters in single mammalian cells. , 1995, Journal of cell science.

[31]  J. W. Hastings,et al.  Chemistries and colors of bioluminescent reactions: a review. , 1996, Gene.

[32]  P. Brick,et al.  Crystal structure of firefly luciferase throws light on a superfamily of adenylate-forming enzymes. , 1996, Structure.

[33]  Jeffrey C. Hall,et al.  Novel Features of Drosophila period Transcription Revealed by Real-Time Luciferase Reporting , 1996, Neuron.

[34]  R. Tsien,et al.  Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescence resonance energy transfer , 1996, Current Biology.

[35]  Andrew J. Millar,et al.  Real-time imaging of transcription in living cells and tissues. , 1996, Biochemical Society transactions.

[36]  M. J. Cormier,et al.  Expression of the Renilla reniformis luciferase gene in mammalian cells. , 1996, Journal of bioluminescence and chemiluminescence.

[37]  M. Maines.  Carbon monoxide and nitric oxide homology: differential modulation of heme oxygenases in brain and detection of protein and activity. , 1996, Methods in enzymology.

[38]  A. Choi,et al.  Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. , 1996, American journal of respiratory cell and molecular biology.

[39]  S Falkow,et al.  Fluorescence-based isolation of bacterial genes expressed within host cells. , 1997, Science.

[40]  S. Kay,et al.  Quantitative Analysis of Drosophila period Gene Transcription in Living Animals , 1997, Journal of biological rhythms.

[41]  J. Stroh,et al.  Identification of a Firefly Luciferase Active Site Peptide Using a Benzophenone-based Photooxidation Reagent* , 1997, The Journal of Biological Chemistry.

[42]  Masafumi Oshiro,et al.  Visualizing Gene Expression in Living Mammals Using a Bioluminescent Reporter , 1997, Photochemistry and photobiology.

[43]  D Gani,et al.  The cleavage activities of aphthovirus and cardiovirus 2A proteins. , 1997, The Journal of general virology.

[44]  S. Falkow,et al.  Probing bacterial gene expression within host cells. , 1997, Trends in microbiology.

[45]  J. F. Atkins,et al.  A dual-luciferase reporter system for studying recoding signals. , 1998, RNA.

[46]  David K. Stevenson,et al.  Bioluminescent indicators in living mammals , 1998, Nature Medicine.

[47]  Taylor,et al.  Imaging bioluminescent indicators shows Ca2+ and ATP permeability thresholds in live cells attacked by complement , 1998, Immunology.

[48]  R Y Tsien,et al.  Specific covalent labeling of recombinant protein molecules inside live cells. , 1998, Science.

[49]  M. Oshiro.  Cooled CCD versus intensified cameras for low-light video--applications and relative advantages. , 1998, Methods in cell biology.

[50]  R. Day,et al.  Dual-function reporter protein for analysis of gene expression in living cells. , 1998, BioTechniques.

[51]  J. Mekalanos,et al.  Systematic identification of essential genes by in vitro mariner mutagenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  R. Tsien,et al.  green fluorescent protein , 2020, Catalysis from A to Z.

[53]  D L Farkas,et al.  Non-invasive image acquisition and advanced processing in optical bioimaging. , 1998, Computerized medical imaging and graphics : the official journal of the Computerized Medical Imaging Society.

[54]  G. Zlokarnik,et al.  beta-lactamase as a marker for gene expression in live zebrafish embryos. , 1998, Developmental biology.

[55]  P. Kelly,et al.  Release factor RF-3 GTPase activity acts in disassembly of the ribosome termination complex. , 1998, RNA.

[56]  S. Falkow,et al.  Flow cytometry and bacterial pathogenesis. , 1998, Current opinion in microbiology.

[57]  R Weissleder,et al.  Preparation of a cathepsin D sensitive near-infrared fluorescence probe for imaging. , 1999, Bioconjugate chemistry.

[58]  C. Contag,et al.  Noninvasive assessment of tumor cell proliferation in animal models. , 1999, Neoplasia.

[59]  David K. Stevenson,et al.  Construction and characterization of a red-emitting luciferase , 1999, Photonics West - Biomedical Optics.

[60]  E. Martínez-Salas.  Internal ribosome entry site biology and its use in expression vectors. , 1999, Current opinion in biotechnology.

[61]  J. Barrio,et al.  Assays for noninvasive imaging of reporter gene expression. , 1999, Nuclear medicine and biology.

[62]  D A Benaron,et al.  Imaging transgenic animals. , 1999, Annual review of biomedical engineering.

[63]  S. Anderson,et al.  Site-directed mutagenesis of firefly luciferase active site amino acids: a proposed model for bioluminescence color. , 1999, Biochemistry.

[64]  Siqing Shan,et al.  Noninvasive visualization of tumors in rodent dorsal skin window chambers , 1999, Nature Biotechnology.

[65]  R Weissleder,et al.  Near-infrared optical imaging of protease activity for tumor detection. , 1999, Radiology.

[66]  J Stables,et al.  Development of a dual glow-signal firefly and Renilla luciferase assay reagent for the analysis of G-protein coupled receptor signalling. , 1999, Journal of receptor and signal transduction research.

[67]  D. Cox,et al.  An action plan for mouse genomics , 1999, Nature Genetics.

[68]  S. L. Chiang,et al.  In vivo genetic analysis of bacterial virulence. , 1999, Annual review of microbiology.

[69]  Y. Ohmiya,et al.  Cloning, sequence analysis, and expression of active Phrixothrix railroad-worms luciferases: relationship between bioluminescence spectra and primary structures. , 1999, Biochemistry.

[70]  J. S. Reynolds,et al.  Imaging of Spontaneous Canine Mammary Tumors Using Fluorescent Contrast Agents , 1999, Photochemistry and photobiology.

[71]  C. Contag,et al.  Visualizing the kinetics of tumor-cell clearance in living animals. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[72]  S. Lukyanov,et al.  Fluorescent proteins from nonbioluminescent Anthozoa species , 1999, Nature Biotechnology.

[73]  P. Dennery,et al.  Regulation and role of heme oxygenase in oxidative injury. , 2000, Current topics in cellular regulation.

[74]  E. Maire,et al.  Development of an ultralow-light-level luminescence image analysis system for dynamic measurements of transcriptional activity in living and migrating cells. , 2000, Analytical biochemistry.

[75]  Meng Yang,et al.  In vivo tumor delivery of the green fluorescent protein gene to report future occurrence of metastasis , 2000, Cancer Gene Therapy.

[76]  G M Rubin,et al.  A brief history of Drosophila's contributions to genome research. , 2000, Science.

[77]  J. Mekalanos,et al.  TnAraOut, A transposon-based approach to identify and characterize essential bacterial genes , 2000, Nature Biotechnology.

[78]  V. Ntziachristos,et al.  Hydrophilic Cyanine Dyes as Contrast Agents for Near-infrared Tumor Imaging: Synthesis, Photophysical Properties and Spectroscopic In vivo Characterization¶ , 2000, Photochemistry and photobiology.

[79]  Stephen M. Mount,et al.  The genome sequence of Drosophila melanogaster. , 2000, Science.

[80]  R Y Tsien,et al.  Biochemistry, mutagenesis, and oligomerization of DsRed, a red fluorescent protein from coral. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[81]  S. Cherry,et al.  PET imaging of transgene expression , 2000, Biological Psychiatry.

[82]  D. Curiel,et al.  A targetable, injectable adenoviral vector for selective gene delivery to pulmonary endothelium in vivo. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  Y Chen,et al.  Novel fluorescent protein from Discosoma coral and its mutants possesses a unique far‐red fluorescence , 2000, FEBS letters.

[84]  Irving L. Weissman,et al.  "Fluorescent timer": protein that changes color with time. , 2000, Science.

[85]  Kevin P. Francis,et al.  Monitoring Bioluminescent Staphylococcus aureusInfections in Living Mice Using a Novel luxABCDEConstruct , 2000, Infection and Immunity.

[86]  Y. Ohmiya,et al.  Bioluminescence Color Determinants of Phrixothrix Railroad-worm Luciferases: Chimeric Luciferases, Site-directed Mutagenesis of Arg 215 and Guanidine effect¶ , 2000 .

[87]  S. Anderson,et al.  The role of lysine 529, a conserved residue of the acyl-adenylate-forming enzyme superfamily, in firefly luciferase. , 2000, Biochemistry.

[88]  A. B. Lyons,et al.  Analysing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution. , 2000, Journal of immunological methods.

[89]  A. Choi,et al.  Heme oxygenase: colors of defense against cellular stress. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[90]  J. Rosenbaum,et al.  Digital video-imaging of leukocyte migration in the iris: intravital microscopy in a physiological model during the onset of endotoxin-induced uveitis. , 2000, Journal of immunological methods.

[91]  C. Contag,et al.  HO-1 expression in type II pneumocytes after transpulmonary gene delivery. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[92]  Eva M. Sevick-Muraca,et al.  Pharmacokinetics of ICG and HPPH-car for the Detection of Normal and Tumor Tissue Using Fluorescence, Near-infrared Reflectance Imaging: A Case Study¶ , 2000, Photochemistry and photobiology.

[93]  A. Campbell,et al.  Targeted bioluminescent indicators in living cells. , 2000, Methods in enzymology.

[94]  Scott E. Fraser,et al.  In vivo visualization of gene expression using magnetic resonance imaging , 2000, Nature Biotechnology.

[95]  V. Ntziachristos,et al.  Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[96]  P. Fossier,et al.  Chimeric green fluorescent protein-aequorin as bioluminescent Ca2+ reporters at the single-cell level. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[97]  Britton Chance,et al.  Breast imaging technology: Probing physiology and molecular function using optical imaging - applications to breast cancer , 2000, Breast Cancer Research.

[98]  L. Svaasand,et al.  Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy. , 2000, Neoplasia.

[99]  Daniel E. Hall,et al.  Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging. , 2000, Neoplasia.

[100]  Daniel J. Hawrysz,et al.  Developments toward diagnostic breast cancer imaging using near-infrared optical measurements and fluorescent contrast agents. , 2000, Neoplasia.

[101]  R Weissleder,et al.  In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. , 2000, Cancer research.

[102]  H. Shimada,et al.  Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[103]  R. Hoffman,et al.  Visualizing gene expression by whole-body fluorescence imaging. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[104]  A. Campbell,et al.  Measurement of proteases using chemiluminescence-resonance-energy-transfer chimaeras between green fluorescent protein and aequorin. , 2001, The Biochemical journal.

[105]  P. Jiang,et al.  Whole-body and intravital optical imaging of angiogenesis in orthotopically implanted tumors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[106]  E. ten Dam,et al.  The 'cleavage' activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring '2A-like' sequences. , 2001, The Journal of general virology.

[107]  Kei Ito,et al.  An Enhanced Mutant of Red Fluorescent Protein DsRed for Double Labeling and Developmental Timer of Neural Fiber Bundle Formation* , 2001, The Journal of Biological Chemistry.

[108]  J. Barrio,et al.  Monitoring gene therapy with reporter gene imaging. , 2001, Seminars in nuclear medicine.

[109]  M. Murtiashaw,et al.  The role of active site residue arginine 218 in firefly luciferase bioluminescence. , 2001, Biochemistry.

[110]  C. Contag,et al.  Bioluminescence imaging of lymphocyte trafficking in vivo. , 2001, Experimental hematology.

[111]  D. Stevenson,et al.  In Vivo Patterns of Heme Oxygenase-1 Transcription , 2001, Journal of Perinatology.

[112]  S. Gambhir,et al.  Optical imaging of Renilla luciferase reporter gene expression in living mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[113]  C. Contag,et al.  Adoptive Immunotherapy of Experimental Autoimmune Encephalomyelitis Via T Cell Delivery of the IL-12 p40 Subunit1 , 2001, The Journal of Immunology.

[114]  H. Ishii,et al.  New Aspects and Mucosal Repair , 2001 .

[115]  Y. Ohmiya,et al.  Thr226 is a key residue for bioluminescence spectra determination in beetle luciferases. , 2001, Biochemical and biophysical research communications.

[116]  Gerald M. Rubin,et al.  The draft sequences: Comparing species , 2001, Nature.

[117]  C. Contag,et al.  Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis. , 2001, The Journal of clinical investigation.

[118]  R. B. Campbell,et al.  In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy , 2001, Nature Medicine.

[119]  A. Loudon,et al.  Persistent synchronized oscillations in prolactin gene promoter activity in living pituitary cells. , 2001, Endocrinology.

[120]  H. Ishii,et al.  In situ demonstration of intraepithelial lymphocyte adhesion to villus microvessels of the small intestine. , 2001, International immunology.

[121]  H. Blau,et al.  In vivo monitoring of myoblast transplantation into rat myocardium. , 2001, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[122]  Ian Parker,et al.  Multiphoton-evoked color change of DsRed as an optical highlighter for cellular and subcellular labeling , 2001, Nature Biotechnology.

[123]  Transparent Window Models and Intravital Microscopy: Imaging Gene Expression, Physiological Function, and Drug Delivery in Tumors , 2001 .

[124]  B. Rice,et al.  In vivo imaging of light-emitting probes. , 2001, Journal of biomedical optics.

[125]  T. Meade.  Seeing is believing. , 2001, Academic radiology.

[126]  D Gani,et al.  Analysis of the aphthovirus 2A/2B polyprotein 'cleavage' mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal 'skip'. , 2001, The Journal of general virology.

[127]  Y. Umezawa,et al.  Split luciferase as an optical probe for detecting protein-protein interactions in mammalian cells based on protein splicing. , 2001, Analytical chemistry.

[128]  R Weissleder,et al.  Optical imaging of matrix metalloproteinase-2 activity in tumors: feasibility study in a mouse model. , 2001, Radiology.

[129]  Y. Wang,et al.  A study of protein-protein interactions in living cells using luminescence resonance energy transfer (LRET) from Renilla luciferase to Aequorea GFP , 2001, Molecular and General Genetics MGG.

[130]  Persistent synchronised oscillations in prolactin gene promoter activity in living pituitary cells: induction by serum shock , 2001 .

[131]  P. Iversen,et al.  Validation of a Noninvasive, Real-Time Imaging Technology Using Bioluminescent Escherichia coli in the Neutropenic Mouse Thigh Model of Infection , 2001, Antimicrobial Agents and Chemotherapy.

[132]  C. Contag,et al.  In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[133]  V. Agol,et al.  Molecular mechanisms of translation initiation in eukaryotes , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[134]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[135]  C. Contag,et al.  Advancing animal models of neoplasia through in vivo bioluminescence imaging. , 2002, European journal of cancer.

[136]  R. Jain,et al.  Conventional and high-speed intravital multiphoton laser scanning microscopy of microvasculature, lymphatics, and leukocyte-endothelial interactions. , 2002, Molecular imaging.

[137]  S S Gambhir,et al.  Noninvasive quantitative imaging of protein–protein interactions in living subjects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[138]  R. Blasberg,et al.  Molecular-genetic imaging: a nuclear medicine-based perspective. , 2002, Molecular imaging.

[139]  Meng Yang,et al.  A highly metastatic Lewis lung carcinoma orthotopic green fluorescent protein model , 2004, Clinical & Experimental Metastasis.

[140]  David K. Stevenson,et al.  Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression , 2001, Transgenic Research.

[141]  R. Lôbo,et al.  Prediction of Transgene integration by Noninvasive Bioluminescent Screening of Microinjected Bovine Embryos , 1998, Transgenic Research.