The Drosophila Broad-Complex plays a key role in controlling ecdysone-regulated gene expression at the onset of metamorphosis

Development ◽  
1993 ◽  
Vol 118 (3) ◽  
pp. 977-988 ◽  
Author(s):  
F.D. Karim ◽  
G.M. Guild ◽  
C.S. Thummel
Keyword(s):  
High Titer ◽  
Polytene Chromosomes ◽  
Solid Substrate ◽  
Primary Response ◽  
Gene Activity ◽  
Secondary Response ◽  
Receptor Protein ◽  
Regulated Gene Expression ◽  
Broad Complex ◽  
Third Instar Larvae

During Drosophila third instar larval development, one or more pulses of the steroid hormone ecdysone activate three temporally distinct sets of genes in the salivary glands, represented by puffs in the polytene chromosomes. The intermolt genes are induced first, in mid-third instar larvae; these genes encode a protein glue used by the animal to adhere itself to a solid substrate for metamorphosis. The intermolt genes are repressed at puparium formation as a high titer ecdysone pulse directly induces a small set of early regulatory genes. The early genes both repress their own expression and activate more than 100 late secondary-response genes. The Broad-Complex (BR-C) is an early ecdysone-inducible gene that encodes a family of DNA binding proteins defined by at least three lethal complementation groups: br, rbp, and l(1)2Bc. We have found that the BR-C is critical for the appropriate regulation of all three classes of ecdysone-inducible genes. Both rbp and l(1)2Bc are required for glue gene induction in mid-third instar larvae. In addition, the l(1)2Bc function is required for glue gene repression in prepupae; in l(1)2Bc mutants the glue genes are re-induced by the late prepupal ecdysone pulse, recapitulating a mid-third instar regulatory response at an inappropriate stage in development. The l(1)2Bc function is also required for the complete ecdysone induction of some early mRNAs (E74A, E75A, and BR-C) and efficient repression of most early mRNAs in prepupae. Like the intermolt secondary-response genes, the late secondary-response genes are absolutely dependent on rbp for their induction. An effect of l(1)2Bc mutations on late gene activity can also be detected, but is most likely a secondary consequence of the submaximal ecdysone-induction of a subset of early regulatory products. Our results indicate that the BR-C plays a key role in dictating the stage-specificity of the ecdysone response. In addition, the ecdysone-receptor protein complex alone is not sufficient for appropriate induction of the early primary-response genes, but requires the prior expression of BR-C proteins. These studies define the BR-C as a key regulator of gene activity at the onset of metamorphosis in Drosophila.

Differential expression of Broad-Complex transcription factors may forecast tissue-specific developmental fates during Drosophila metamorphosis

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3275-3287 ◽  
Author(s):  
I.F. Emery ◽  
V. Bedian ◽  
G.M. Guild
Keyword(s):  
Western Blot ◽  
Expression Patterns ◽  
Primary Response ◽  
Protein Isoforms ◽  
Secondary Response ◽  
C Protein ◽  
Tissue Specific ◽  
Specific Outcome ◽  
C Proteins ◽  
Broad Complex

The steroid hormone ecdysone initiates metamorphosis in Drosophila melanogaster by activating a cascade of gene activity that includes primary response transcriptional regulators and secondary response structural genes. The Broad-Complex (BR-C) primary response gene is composed of several distinct genetic functions and encodes a family of related transcription factor isoforms. Our objective was to determine whether BR-C isoforms were components of the primary ecdysone response in all tissues and whether tissue-specific isoform expression is associated with tissue-specific metamorphic outcomes. We used specific antibody reagents that recognize and distinguish among the Z1, Z2 and Z3 BR-C protein isoforms to study protein expression patterns during the initial stages of metamorphosis. Western blot analyses demonstrated that BR-C isoforms are induced at the onset of metamorphosis, each with unique kinetics of induction and repression. Whole-mount immunostaining showed that the BR-C proteins accumulate in the nuclei of all larval and imaginal tissues indicating that the BR-C is induced as a primary response in many tissues. Several tissues express different levels and combinations of the BR-C isoforms suggesting that the BR-C is important in determining the tissue-specific outcome of many parallel ecdysone response cascades. For example, prepupal salivary glands (destined for histolysis during metamorphosis) express Z1 isoforms while imaginal discs (destined for cell differentiation and morphogenesis) shift from the synthesis of Z2 isoforms to the synthesis of Z1 isoforms. The prepupal central nervous system (destined for tissue remodeling) expresses all isoforms, with Z3 predominating. Salivary gland chromosome immunostaining indicated that BR-C proteins interact directly with numerous loci in the polytene genome. Finally, western blot analyses showed that distinct BR-C genetic functions can be correlated with single and specific BR-C protein isoforms.

scholarly journals The ecdysone-inducible Broad-complex and E74 early genes interact to regulate target gene transcription and Drosophila metamorphosis.

Genetics ◽  
1995 ◽  
Vol 141 (3) ◽  
pp. 1025-1035 ◽  
Author(s):  
J C Fletcher ◽  
C S Thummel
Keyword(s):  
Transcription Factors ◽  
Gene Transcription ◽  
Synergistic Effects ◽  
Group Analysis ◽  
Complementation Group ◽  
Primary Response ◽  
Early Gene ◽  
Secondary Response ◽  
Insect Metamorphosis ◽  
Broad Complex

Abstract Pulses of the steroid hormone ecdysone initiate Drosophila metamorphosis by inducing widespread changes in gene expression. The Broad-Complex (BR-C) and E74 are induced directly by ecdysone and encode families of transcription factors that regulate ecdysone primary- and secondary-response genes. Genetic analyses have revealed that mutations in the BR-C and E74 are lethal during metamorphosis and that these mutations cause some similar lethal phenotypes and alterations in secondary-response gene transcription. To examine whether the BR-C and E74 function together during development, we have combined representative alleles from each BR-C and E74 complementation group. Analysis of the morphological and molecular phenotypes of the double-mutant animals reveals that BR-C and E74 alleles act together to produce both novel and synergistic effects. We find that the BR-C and E74 share functions in puparium formation, pupation and early gene induction. In addition, our evidence suggests that the BR-C and E74 transcription factors may directly interact to regulate the expression of salivary gland glue and late genes. This data is consistent with current models which propose that combinations of ecdysone primary-response genes regulate common morphogenetic pathways during insect metamorphosis.

scholarly journals POS0461 RESPONSE TO BIOLOGIC THERAPY IN RHEUMATOID ARTHRITIS: RETHINKING OUR CLASSIFICATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 462.1-462
Author(s):  
E. Vallejo-Yagüe ◽  
S. Kandhasamy ◽  
E. Keystone ◽  
A. Finckh ◽  
R. Micheroli ◽  
...  
Keyword(s):  
Treatment Response ◽  
Real World ◽  
Observational Studies ◽  
Initial Response ◽  
Primary Response ◽  
Sustained Response ◽  
Secondary Response ◽  
Real World Data ◽  
World Data ◽  
Secondary Failure

Background:In rheumatoid arthritis (RA), primary failure with biologic treatment may be understood as lack of initial clinical response, while secondary failure would be loss of effectiveness after an initial response. Despite these clinical concepts, there is no unifying operational definition of primary and secondary non-response to RA treatment in observational studies using real-world data. On top of data-driven challenges, when conceptualizing secondary non-responders, it is unclear if the mechanism behind loss of effectiveness after a brief initial response is similar to loss of effectiveness after previous benefit sustained over time.Objectives:This viewpoint aims to motivate discussion on how to define primary and secondary non-response in observational studies. Ultimately, we aim to trigger expert committees to develop standard terminology for these concepts.Methods:We discuss different methodologies for defining primary and secondary non-response in observational studies. To do so, we shortly overview challenges characteristic of performing observational studies in real-world data, and subsequently, we conceptualize whether treatment response should be a dichotomous classification (Primary response/non-response; Secondary response/non-response), or whether one should consider three response categories (Primary response/non-response; Primary sustained/non-sustained response; Secondary response/non-response).Results:RA or biologic registries are a common data source for studying treatment response in real-world data. While registries include disease-specific variables to assess disease progression, missing data, loss of follow-up, and visits restricted to the year or mid-year visit may present a challenge. We believe there is a general agreement to assess primary response within the first 6 month of treatment. However, conceptualizing secondary non-response, one could wonder if a patient with brief initial response and immediate loss of it should belong to the same response category as a patient who relapses after a period of prior benefit that was sustained over time. Until this concern is clarified, we recommend considering a period of sustained response as a pre-requisite for secondary failure. This would result in the following three categories: a) Primary non-response: Lack of response within the first 6 months of treatment; b) Primary sustained response: Maintenance of a positive effectiveness outcome for at least the first 12 months since treatment start; c) Secondary non-response: Loss of effectiveness after achieved primary sustained response. Figure 1 illustrates this classification through a decision tree. Since the underlying mechanisms for treatment failure may differ among the above-mentioned categories, we recommend to use the three-category classification. However, since this may pose additional methodological challenges in real-world data, optionally, a dichotomous 12-month time-point may be used to assess secondary non-response (unfavourable outcome after 12-months) in comparison to primary non-response or non-sustained response (unfavourable outcome within the first 12-months). Similarly, to study primary response, the solely 6-month timepoint may be used.Conclusion:A unified operational definition of treatment response will minimize heterogeneity among observational studies and help improve the ability to draw cross-study comparisons, which we believe would be of particular interest when identifying predictors of treatment failure. Thus, we hope to open the room for discussion and encourage expert committees to work towards a common approach to assess treatment primary and secondary non-response in RA in observational studies.Disclosure of Interests:Enriqueta Vallejo-Yagüe: None declared, Sreemanjari Kandhasamy: None declared, Edward Keystone Speakers bureau: Amgen, AbbVie, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Novartis, Pfizer Pharmaceuticals, Sanofi Genzyme, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb Company, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis, Grant/research support from: Amgen, Merck, Pfizer Pharmaceuticals, PuraPharm, Axel Finckh Speakers bureau: Pfizer, Eli-Lilly, Paid instructor for: Pfizer, Eli-Lilly, Consultant of: AbbVie, AB2Bio, BMS, Gilead, Pfizer, Viatris, Grant/research support from: Pfizer, BMS, Novartis, Raphael Micheroli Consultant of: Gilead, Eli-Lilly, Pfizer and Abbvie, Andrea Michelle Burden: None declared

Cognate CD4 help is essential for the reactivation and expansion of CD8 memory T cells directed against the hematopoietic cell–specific dominant minor histocompatibility antigen, H60

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4273-4280 ◽  
Author(s):  
Su Jeong Ryu ◽  
Kyung Min Jung ◽  
Hyun Seung Yoo ◽  
Tae Woo Kim ◽  
Sol Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Primary Response ◽  
Hematopoietic Cell ◽  
Secondary Response ◽  
Memory Cd8 T Cells ◽  
Specific Memory ◽  
Cd4 Help ◽  
Different Response

AbstractIn contrast to previous notions of the help-independency of memory CD8 T cells during secondary expansion, here we show that CD4 help is indispensable for the re-expansion of once-helped memory CD8 T cells, using a hematopoietic cell–specific dominant minor histocompatibility (H) antigen, H60, as a model antigen. H60-specific memory CD8 T cells generated during a helped primary response vigorously expanded only when rechallenged under helped conditions. The help requirement for an optimal secondary response was confirmed by a reduction in peak size by CD4 depletion, and was reproduced after skin transplantation. Helpless conditions or noncognate separate help during the secondary response resulted in a significant reduction in the peak size and different response kinetics. Providing CD4 help again during a tertiary challenge restored robust memory expansion; however, the repeated deprivation of help further reduced clonal expansion. Adoptively transferred memory CD8 T cells did not proliferate in CD40L−/− hosts. In the CD40−/− hosts, marginal memory expansion was detected after priming with male H60 cells but was completely abolished by priming with peptide-loaded CD40−/− cells, suggesting the essential role of CD40 and CD40L in memory responses. These results provide insight into the control of minor H antigen-specific CD8 T-cell responses, to maximize the graft-versus-leukemia response.

scholarly journals Impacts of dietary exposure to sodium or potassium salts of nitrate and nitrite on the development of Drosophila melanogaster

2017 ◽  
Vol 10 (2) ◽  
pp. 70-78 ◽  
Author(s):  
Ashim Kumar Basak ◽  
Tridip Chatterjee ◽  
Swapan Kumar Ghosh ◽  
Amit Chakravarty
Keyword(s):  
Young Adults ◽  
Food Additives ◽  
Polytene Chromosomes ◽  
Model Organism ◽  
Developmental Outcomes ◽  
Dietary Exposure ◽  
Potassium Nitrate ◽  
Toxicological Studies ◽  
Nitrate And Nitrite ◽  
Third Instar Larvae

AbstractThe effects of four food additives, namely sodium nitrite (NaNO2), sodium nitrate (NaNO3), potassium nitrite (KNO2), and potassium nitrate (KNO3), on animal development were evaluated by using Drosophila melanogster, a model organism. Adult male and female flies were allowed to breed in culture medium, each containing one of 4 concentrations,i.e.10, 20, 30 or 40 mM of the above mentioned salts. The concentration of 40 mM, NaNO2and KNO2 completely arrested the development of the flies. Of the different concentrations of the four salts tested, exposure of flies to 30 mM NaNO2exhibited only significant delays in the initial appearances of third instar larvae, pupae and young adults, along with huge reduction in the number of pupae and young adults compared to controls. Rearrangements like inversions, deletion looping, regional shrinking, as well as highly enlarged puffing,etc.were also observed in the polytene chromosomes of the third instar larvae exposed to 30 mM NaNO2. Developmental outcomes of the flies exposed to varying concentrations of NaNO3and KNO3 did not differ significantly from the controls. Owing to the extensive genetic homology between Drosophila and human and the successful uses of this fly as models in developmental and toxicological studies, we speculate that the experimental results exhibited by this organism in our study strongly advocate for abstaining from the dietary use of NaNO2and KNO2 during human pregnancies to avoid possible negative developmental outcomes.

scholarly journals Modified LDL Particles Activate Inflammatory Pathways in Monocyte-derived Macrophages: Transcriptome Analysis

2018 ◽  
Vol 24 (26) ◽  
pp. 3143-3151 ◽  
Author(s):  
Alexander N. Orekhov ◽  
Yumiko Oishi ◽  
Nikita G. Nikiforov ◽  
Andrey V. Zhelankin ◽  
Larisa Dubrovsky ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Primary Response ◽  
Secondary Response ◽  
Modified Ldl ◽  
Ldl Particles ◽  
Regulator Genes ◽  
Lipid Metabolism Genes

Background: A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation. Methods: We attempted to identify the main mater regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. Results: We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL- 15 and CXCL8. Conclusion: Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.

scholarly journals EVOLUTION OF THE IMMUNE RESPONSE

1964 ◽  
Vol 119 (1) ◽  
pp. 105-130 ◽  
Author(s):  
Ben W. Papermaster ◽  
Richard M. Condie ◽  
Joanne Finstad ◽  
Robert A. Good
Keyword(s):  
Adaptive Immunity ◽  
Primary Response ◽  
Antigenic Stimulation ◽  
Secondary Response ◽  
Immunologic Reactivity ◽  
Starch Gel ◽  
Eptatretus Stoutii ◽  
Amia Calva ◽  
Secondary Stimulation ◽  
Bacteriophage T2

1. The California hagfish, Eptatretus stoutii, seems to be completely lacking in adaptive immunity: it forms no detectable circulating antibody despite intensive stimulation with a range of antigens; it does not show reactivity to old tuberculin following sensitization with BCG; and gives no evidence of homograft immunity. 2. Studies on the sea lamprey, Petromyzon marinus, have been limited to the response to bacteriophage T2 and hemocyanin in small groups of spawning animals. They suggest that the lamprey may have a low degree of immunologic reactivity. 3. One holostean, the bowfin (Amia calva) and the guitarfish (Rhinobatos productus), an elasmobranch, showed a low level of primary response to phage and hemocyanin. The response is slow and antibody levels low. Both the bowfin and the guitarfish showed a vigorous secondary response to phage, but neither showed much enhancement of reactivity to hemocyanin in the secondary response. The bowfin formed precipitating antibody to hemocyanin, but the guitarfish did not. Both hemagglutinating and precipitating antibody to hemocyanin were also observed in the primary response of the black bass. 4. The bowfin was successfully sensitized to Ascaris antigen, and lesions of the delayed type developed after challenge at varying intervals following sensitization. 5. The horned shark (Heterodontus franciscii) regularly cleared hemocyanin from the circulation after both primary and secondary antigenic stimulation, and regularly formed hemagglutinating antibody, but not precipitating antibody, after both primary and secondary stimulation with this antigen. These animals regularly cleared bacteriophage from the circulation after both the primary and secondary stimulation with bacteriophage T2. Significant but small amounts of antibody were produced in a few animals in the primary response, and larger amounts in the responding animals after secondary antigenic stimulation. 6. Studies by starch gel and immunoelectrophoresis show that the hagfish has no bands with mobilities of mammalian gamma globulins; that the lamprey has a single, relatively faint band of this type; and that multiple gamma bands are characteristic of the holostean, elasmobranchs, and teleosts studied. By this method of study, the bowfin appeared to have substantial amounts of gamma2 globulin. 7. We conclude that adaptive immunity and its cellular and humoral correlates developed in the lowest vertebrates, and that a rising level of immunologic reactivity and an increasingly differentiated and complex immunologic mechanism are observed going up the phylogenetic scale from the hagfish, to the lamprey, to the elasmobranchs, to the holosteans, and finally the teleosts.

scholarly journals Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and Broad-Complex gene activity

2003 ◽  
Vol 259 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Lorenzo F Sempere ◽  
Nicholas S Sokol ◽  
Edward B Dubrovsky ◽  
Edward M Berger ◽  
Victor Ambros
Keyword(s):  
Drosophila Melanogaster ◽  
Microrna Expression ◽  
Gene Activity ◽  
Temporal Regulation ◽  
Broad Complex

scholarly journals Personalised Profiling of Innate Immune Memory Induced by Nano-Imaging Particles in Human Monocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Giacomo Della Camera ◽  
Mariusz Madej ◽  
Anna Maria Ferretti ◽  
Rita La Spina ◽  
Yang Li ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Primary Response ◽  
Innate Immune ◽  
Engineered Nanoparticles ◽  
Secondary Response ◽  
Immune Memory ◽  
Immune Reactivity ◽  
Iron Oxide Particles ◽  
Lps Challenge

Engineered nanoparticles used for medical purposes must meet stringent safety criteria, which include immunosafety, i.e., the inability to activate possibly detrimental immune/inflammatory effects. Even medical nanomaterials devoid of direct immunotoxic or inflammatory effects may have an impact on human health if able to modify innate memory, which is the ability to “prime” future immune responses towards a different, possibly more detrimental reactivity. Although innate memory is usually protective, anomalous innate memory responses may be at the basis of immune pathologies. In this study, we have examined the ability of two nanomaterials commonly used for diagnostic imaging purposes, gold and iron oxide nanoparticles, to induce or modulate innate memory, using an in vitro model based on human primary monocytes. Monocytes were exposed in culture to nanoparticles alone or together with the bacterial agent LPS (priming phase/primary response), then rested for six days (extinction phase), and eventually challenged with LPS (memory/secondary response). The memory response to the LPS challenge was measured as changes in the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra), as compared to unprimed monocytes. The results show that both types of nanoparticles can have an effect in the induction of memory, with changes observed in the cytokine production. By comparing nanomaterials of different shapes (spherical vs. rod-shaped gold particles) and different size (17 vs. 22 nm diameter spherical iron oxide particles), it was evident that innate memory could be differentially induced and modulated depending on size, shape and chemical composition. However, the main finding was that the innate memory effect of the particles was strongly donor-dependent, with monocytes from each donor showing a distinct memory profile upon priming with the same particles, thereby making impossible to draw general conclusions on the particle effects. Thus, in order to predict the effect of imaging nanoparticles on the innate memory of patients, a personalised profiling would be required, able to take in consideration the peculiarities of the individual innate immune reactivity.

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