A Live Zebrafish-Based Screening System for Human Nuclear Receptor Ligand and Cofactor Discovery
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Mendeley | Further Information

{"title"=>"A live zebrafish-based screening system for human nuclear receptor ligand and cofactor discovery", "type"=>"journal", "authors"=>[{"first_name"=>"Jens", "last_name"=>"Tiefenbach", "scopus_author_id"=>"6603409456"}, {"first_name"=>"Pamela R.", "last_name"=>"Moll", "scopus_author_id"=>"57197302961"}, {"first_name"=>"Meryl R.", "last_name"=>"Nelson", "scopus_author_id"=>"7403461808"}, {"first_name"=>"Chun", "last_name"=>"Hu", "scopus_author_id"=>"8419741700"}, {"first_name"=>"Lilia", "last_name"=>"Baev", "scopus_author_id"=>"37001671800"}, {"first_name"=>"Thomas", "last_name"=>"Kislinger", "scopus_author_id"=>"6603611520"}, {"first_name"=>"Henry M.", "last_name"=>"Krause", "scopus_author_id"=>"7202403521"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"doi"=>"10.1371/journal.pone.0009797", "sgr"=>"77955053756", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"20339547", "issn"=>"19326203", "scopus"=>"2-s2.0-77955053756", "pui"=>"368261725"}, "id"=>"723df881-5f36-3d17-9823-dead8b09468a", "abstract"=>"Nuclear receptors (NRs) belong to a superfamily of transcription factors that regulate numerous homeostatic, metabolic and reproductive processes. Taken together with their modulation by small lipophilic molecules, they also represent an important and successful class of drug targets. Although many NRs have been targeted successfully, the majority have not, and one third are still orphans. Here we report the development of an in vivo GFP-based reporter system suitable for monitoring NR activities in all cells and tissues using live zebrafish (Danio rerio). The human NR fusion proteins used also contain a new affinity tag cassette allowing the purification of receptors with bound molecules from responsive tissues. We show that these constructs 1) respond as expected to endogenous zebrafish hormones and cofactors, 2) facilitate efficient receptor and cofactor purification, 3) respond robustly to NR hormones and drugs and 4) yield readily quantifiable signals. Transgenic lines representing the majority of human NRs have been established and are available for the investigation of tissue- and isoform-specific ligands and cofactors.", "link"=>"http://www.mendeley.com/research/live-zebrafishbased-screening-system-human-nuclear-receptor-ligand-cofactor-discovery", "reader_count"=>56, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>21, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Other"=>4, "Student > Master"=>4, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>21, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Other"=>4, "Student > Master"=>4, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Environmental Science"=>3, "Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>39, "Neuroscience"=>2, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Neuroscience"=>{"Neuroscience"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>39}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>5}, "Environmental Science"=>{"Environmental Science"=>3}}, "reader_count_by_country"=>{"United States"=>1, "Germany"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/857697"], "description"=>"<p>(<b>a</b>) Dose dependent GFP expression Shown are the dose responses for T<sub>3</sub>, KB2115 and TRIAC in TRβ tail epidermis (48 hpf) treated embryos. Treatments were done from 0.1–500 nM. GFP images show anterior-posterior tail view (imaged at 150× magnification) (<b>b</b>) The graph indicates average intensity of GFP signals for each treatment in percent. GFP expression was quantified using nuclei count software from MetaX files. Values for drug treated fish are shown in yellow (TRIAC), in blue (KB2115) and in red (T<sub>3</sub>).</p>", "links"=>[], "tags"=>["responses"], "article_id"=>528147, "categories"=>["Cell Biology", "Medicine", "Infectious Diseases", "Genetics", "Pharmacology", "Developmental Biology", "Molecular Biology"], "users"=>["Jens Tiefenbach", "Pamela R. Moll", "Meryl R. Nelson", "Chun Hu", "Lilia Baev", "Thomas Kislinger", "Henry M. Krause"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009797.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_LT_drug_responses_are_quantifiable_/528147", "title"=>"LT drug responses are quantifiable.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-22 02:15:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/857285"], "description"=>"<p>Transgenic NR zebrafish show unique GFP patterns at different stages of development. Activity patterns of the PPARγ (first panel), RORγ (middle panel), NOR1 (upper right picture) and Rev-erbα (lower right picture) LT constructs. Embryos were heat pulsed at 37°C for 30 min and images taken 24 h later. PPARγ (48 hpf, F2) embryos show GFP expression in cells of the epidermis and heart, as well as in the posterior spinal cord. Strong GFP expression occurs in the epidermis and retina of RORγ embryos (72 hpf, F2). NOR1 embryos (F3) express GFP in the posterior spinal cord, hatching gland, epidermis and yolk syncictial layer (24 hpf, F2). Rev-erbα embryos show no GFP expression. Overlay pictures of bright field and GFP (75% transparent) are shown. Views are lateral with anterior to the left.</p>", "links"=>[], "tags"=>["nrs", "ligands"], "article_id"=>527732, "categories"=>["Cell Biology", "Medicine", "Infectious Diseases", "Genetics", "Pharmacology", "Developmental Biology", "Molecular Biology"], "users"=>["Jens Tiefenbach", "Pamela R. Moll", "Meryl R. Nelson", "Chun Hu", "Lilia Baev", "Thomas Kislinger", "Henry M. Krause"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009797.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Human_NRs_interact_with_fish_ligands_and_cofactors_/527732", "title"=>"Human NRs interact with fish ligands and cofactors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-22 02:08:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/857843"], "description"=>"<p>Schematic representation of LT platform functions.</p>", "links"=>[], "tags"=>["lt"], "article_id"=>528294, "categories"=>["Cell Biology", "Medicine", "Infectious Diseases", "Genetics", "Pharmacology", "Developmental Biology", "Molecular Biology"], "users"=>["Jens Tiefenbach", "Pamela R. Moll", "Meryl R. Nelson", "Chun Hu", "Lilia Baev", "Thomas Kislinger", "Henry M. Krause"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009797.g006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_representation_of_LT_platform_functions_/528294", "title"=>"Schematic representation of LT platform functions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-22 02:18:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/426276", "https://ndownloader.figshare.com/files/426298", "https://ndownloader.figshare.com/files/426333", "https://ndownloader.figshare.com/files/426363"], "description"=>"<div><p>Nuclear receptors (NRs) belong to a superfamily of transcription factors that regulate numerous homeostatic, metabolic and reproductive processes. Taken together with their modulation by small lipophilic molecules, they also represent an important and successful class of drug targets. Although many NRs have been targeted successfully, the majority have not, and one third are still orphans. Here we report the development of an <em>in vivo</em> GFP-based reporter system suitable for monitoring NR activities in all cells and tissues using live zebrafish (<em>Danio rerio</em>). The human NR fusion proteins used also contain a new affinity tag cassette allowing the purification of receptors with bound molecules from responsive tissues. We show that these constructs 1) respond as expected to endogenous zebrafish hormones and cofactors, 2) facilitate efficient receptor and cofactor purification, 3) respond robustly to NR hormones and drugs and 4) yield readily quantifiable signals. Transgenic lines representing the majority of human NRs have been established and are available for the investigation of tissue- and isoform-specific ligands and cofactors.</p></div>", "links"=>[], "tags"=>["zebrafish-based", "receptor", "ligand", "cofactor"], "article_id"=>144152, "categories"=>["Cell Biology", "Medicine", "Cancer", "Genetics", "Pharmacology", "Developmental Biology", "Molecular Biology"], "users"=>["Jens Tiefenbach", "Pamela R. Moll", "Meryl R. Nelson", "Chun Hu", "Lilia Baev", "Thomas Kislinger", "Henry M. Krause"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0009797.s001", "https://dx.doi.org/10.1371/journal.pone.0009797.s002", "https://dx.doi.org/10.1371/journal.pone.0009797.s003", "https://dx.doi.org/10.1371/journal.pone.0009797.s004"], "stats"=>{"downloads"=>13, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Live_Zebrafish_Based_Screening_System_for_Human_Nuclear_Receptor_Ligand_and_Cofactor_Discovery/144152", "title"=>"A Live Zebrafish-Based Screening System for Human Nuclear Receptor Ligand and Cofactor Discovery", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-03-22 01:09:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/857553"], "description"=>"<p>(<b>a</b>) LT-PPARγ embryos show strong reporter activation in the presence of receptor specific agonist (uses as indicated). After heat pulse followed by overnight incubation with solvent or drug GFP expression in cells of the epidermis, CNS, eye, blood and heart (48 hpf; lateral view) is induced. Yellow arrow indicates GFP expression in heart. (<b>b</b>) Upper panel shows magnifications of embryo heads in ventral (b-1-2) and dorsal (b-3-4) orientation of 2 dpf fish treated with solvent or 50 nM Rosiglitazone (RGZ). B-2 shows reporter expression in eye (e), forebrain (fb), heart (h) and b-4 indicates GFP expression in hindbrain (hb), tectum (t) and anterior spinal cord (s). Middle panel shows drug responses in tissues of older embryos: Expression in heart (b-5; 5 dpf ventral view), in blood (b-6; 8 dpf), in the spinal cord (s) and endothelium layer ((el), b-7; 4 dpf, lateral view) and in the intestine ((I, b-8; 6 dpf). Embryos were subjected to a 30 minute heat pulse at 37°C, followed by incubation with 50 nM Rosiglitazone for 24 h. The lower panels show responses to: endogenous hormone in the tail epidermis of 3 dpf embryos treated with solvent (b-9); 500 nM Pioglitazone (b-11), 500 nM RGZ (b-12) and treatment with the antagonist GW9662 (500 nM). (<b>c</b>) TRβ LT embryos show tissue-specific responses to hormones and drugs. After 40 min heat induction, embryos (24 hpf) were incubated with compounds for 28 h in a 28°C incubator in the dark. Solvent (Ethanol) treated embryos show no GFP expression. T<sub>4</sub> (2.5 µM) treated embryos show strong reporter activity in muscle and to a lesser amount in epidermis, brain and eye retina. T<sub>3</sub> (2.5 µM) treatments result in similar responses but GFP induction in epidermis, brain and eye is stronger, and signal is also seen in blood cells. TRIAC (100 nM) treatments also induce GFP responses in brain, heart, eye, epidermis and muscle, and in addition, anterior spinal cord. Overlay pictures of bright field and GFP (75% transparent) are shown. Arrows indicate tissue-specific GFP responses: grey  =  muscle and red  =  brain. (<b>d</b>) TRβ responses in transgenic fish are dependent on a functional LBD. TRβ<sub>wt</sub>, TRβ<sub>E457A</sub> and TRβ<sub>dAF2</sub> embryos (24 hfp, F1) were heat pulsed and soaked in TRIAC (100 nM) as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009797#pone-0009797-g004\" target=\"_blank\">Figure 4c</a>. The upper row shows strong (wt), weak (E457A) and no (dAF2) epidermal GFP expression in the tail. Western blot detected proteins show similar levels of TRβ transgene expression (right side).</p>", "links"=>[], "tags"=>["activities", "responsive", "snrm"], "article_id"=>527996, "categories"=>["Cell Biology", "Medicine", "Infectious Diseases", "Genetics", "Pharmacology", "Developmental Biology", "Molecular Biology"], "users"=>["Jens Tiefenbach", "Pamela R. Moll", "Meryl R. Nelson", "Chun Hu", "Lilia Baev", "Thomas Kislinger", "Henry M. Krause"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009797.g004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ligand_trap_activities_are_drug_responsive_and_reveal_SNRM_activities_/527996", "title"=>"Ligand trap activities are drug responsive and reveal SNRM activities.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-22 02:13:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/857416"], "description"=>"<p>(<b>a</b>) Affinity purification of TRβ from zebrafish embryos. Blastula-/Gastrula-stage embryos were heat induced for 20 min and recovered for 2 h at room temperature. After purification, the eluate was run on an 8% SDS PAGE and then silver stained. Protein bands (indicated as 1–6) were cut and in gel digested followed by mass spectrometry. Identified protein IDs are shown. M =  protein marker. (<b>b</b>) Immunodetection of HIPK3. Western blotting using a HIPK3 antibody (lower panel) shows that a subfraction of the protein co-purifies with the bait protein. Presence of the TRβ protein in the same fractions, detected using Flag-M2 antibody, is shown above. (<b>c</b>) HEK293 cells were transfected with FLAG-HIPK3 and one of three different Gal expression constructs containing the FSH-tag: Gal, Gal-TRβ (aa 189–461) and TRβ<sub>ΔAF2</sub> (aa 189–451). After 48 h of transfection, the cells were harvested in IP buffer and Gal and Gal fusion proteins immunoprecipitated using Streptactin Sepharose. Western blotting using a FLAG M2 antibody shows HIPK3 in the Gal-TRβ and Gal-TRβ<sub>ΔAF2</sub> pull downs. (<b>d</b>) Transcriptional activity of <b>T</b>Rβ proteins. 293 cells were transfected with a 2xUAS-Luciferase reporter construct (0.2 µg/well) and Gal or Gal-TRβ constructs (0.05 µg/well): Gal-TRβ (aa 189–461) and TRβ<sub>ΔAF2</sub> (aa 189–451) in the presence of 100 nM TRIAC. Fold activation was measured in the presence (0.05 or 0.1 µg/well) or absence of HIPK3. Luciferase values were normalized against β-Gal. (<b>e</b>) Effects of HIPK3 on Gal-TRβ induced repression. 293 cells were transfected with a 2xUAS-Luciferase reporter construct and either Gal, Gal-TRβ or GAL-TRβ<sub>ΔAF2</sub>. Fold repression was measured in the presence or absence of HIPK3. Luciferase values were normalized against β-Gal. Transfections as under 3d. (<b>f</b>) The effect of HIPK3 was investigated in the absence or presence of the co-repressor N-CoR. Transfections were performed as in 3d using the Gal-TRβ<sub>ΔAF2</sub> (aa 189–451) construct. Fold repression of the TRβ mutant in the presence of HIPK3 and/or N-CoR (0.05 µg/well) are shown.</p>", "links"=>[], "tags"=>["molecular biology", "biotechnology/protein chemistry and proteomics", "cell biology/developmental molecular mechanisms", "developmental biology/developmental molecular mechanisms", "developmental biology/pattern formation", "genetics and genomics/gene function", "diabetes and endocrinology/endocrinology", "diabetes and endocrinology/thyroid", "pharmacology/drug development"], "article_id"=>527852, "categories"=>["Cell Biology", "Medicine", "Infectious Diseases", "Genetics", "Pharmacology", "Developmental Biology", "Molecular Biology"], "users"=>["Jens Tiefenbach", "Pamela R. Moll", "Meryl R. Nelson", "Chun Hu", "Lilia Baev", "Thomas Kislinger", "Henry M. Krause"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009797.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Co_purification_of_TR_946_cofactors_/527852", "title"=>"Co-purification of TRβ cofactors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-22 02:10:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/857195"], "description"=>"<p>(<b>a</b>) Schematic diagram of the multi-component ligand trap (LT) construct. Upon heat pulse, the zebrafish <i>hsp70</i> promoter directs ubiquitous expression of the GAL4 DNA-binding domain (DBD) fused in-frame to a <i>human</i> nuclear receptor ligand-binding domain (LBD) and an affinity tag cassette (FSH-tag). Upon binding of this fusion protein to the GAL4 UAS (upstream activating sequence) response elements, in the presence of active hormone and cofactors, expression of the reporter gene (nuclear enhanced Green Fluorescent Protein (eGFP)) occurs. Expression of nuclear GFP is used to monitor receptor ligand sensor activity in a cell- and tissue autonomous manner in live zebrafish. The second component makes use of the tags to co-purify bound hormones or cofactors. I  =  insulator elements; pA  =  polyadenylation signal; NLS  =  nuclear localization signal. (<b>b</b>) Western blots of GAL4-NR fusion proteins. Embryos (F2; 72 hpf) were heat pulsed for 30 min at 37°C and recovered for 1 h at room temperature. 10 embryos were pooled and lysed in 50 µl of FSH buffer (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009797#s4\" target=\"_blank\">material and methods</a>) followed by adding SDS buffer and boiling. Proteins were detected using the FLAG-M2 antibody. (<b>c</b>) Time course of fusion protein expression. TRβ embryos (F2; 72 hpf) were heat induced as in 1b) and recovered for the times indicated. Each sample contained 10 embryos.</p>", "links"=>[], "tags"=>["ligand"], "article_id"=>527630, "categories"=>["Cell Biology", "Medicine", "Infectious Diseases", "Genetics", "Pharmacology", "Developmental Biology", "Molecular Biology"], "users"=>["Jens Tiefenbach", "Pamela R. Moll", "Meryl R. Nelson", "Chun Hu", "Lilia Baev", "Thomas Kislinger", "Henry M. Krause"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009797.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Ligand_Trap_LT_system_/527630", "title"=>"The Ligand Trap (LT) system.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-03-22 02:07:10"}

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