Competitive interactions between cells are the basis of many homeostatic processes in biology. Some of the best-described cases of competition between cells occur in DROSOPHILA: cell competition, ...whereby somatic cells within a growing epithelium compete with one another for contribution to the adult, and stem cell competition, in which germline or somatic stem cells vie for residency in the niche. Both types of competition are conserved physiological processes, with much to tell us about how cellular neighborhoods influence cell behavior, and have importance to stem cell biology, regeneration and transplantation, and cancer.
Cell competition employs comparisons of fitness to selectively eliminate cells sensed as less healthy. In Drosophila, apoptotic elimination of the weaker “loser” cells from growing wing discs is ...induced by a signaling module consisting of the Toll ligand Spätzle (Spz), several Toll-related receptors, and NF-κB factors. How this module is activated and restricted to competing disc cells is unknown. Here, we use Myc-induced cell competition to demonstrate that loser cell elimination requires local wing disc synthesis of Spz. We identify Spz processing enzyme (SPE) and modular serine protease (ModSP) as activators of Spz-regulated competitive signaling and show that “winner” cells trigger elimination of nearby WT cells by boosting SPE production. Moreover, Spz requires both Toll and Toll-8 to induce apoptosis of wing disc cells. Thus, during cell competition, Spz-mediated signaling is strictly confined to the imaginal disc, allowing errors in tissue fitness to be corrected without compromising organismal physiology.
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•In Myc super-competition, Spz signals via Toll and Toll-8 to kill loser cells•Spz is activated for competitive signaling by the proteases SPE and ModSP•Regulation of protease production and receptor expression by Myc allows “cheating”•Wing disc-restricted Spz keeps competitive signaling isolated from immune tissues
Low levels of the Toll ligand Spätzle and its activating proteases are synthesized continuously by wing disc cells, but signaling is unproductive. Alpar et al. show that Myc super-competitor cells boost production of the proteases, thereby triggering Spätzle activation and inducing a killing signal that selectively eliminates nearby wild-type cells.
Mosaic Analysis in Drosophila Germani, Federico; Bergantinos, Cora; Johnston, Laura A
Genetics (Austin),
02/2018, Letnik:
208, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Since the founding of
genetics by Thomas Hunt Morgan and his colleagues over 100 years ago, the experimental induction of mosaicism has featured prominently in its recognition as an unsurpassed ...genetic model organism. The use of genetic mosaics has facilitated the discovery of a wide variety of developmental processes, identified specific cell lineages, allowed the study of recessive embryonic lethal mutations, and demonstrated the existence of cell competition. Here, we discuss how genetic mosaicism in
became an invaluable research tool that revolutionized developmental biology. We describe the prevailing methods used to produce mosaic animals, and highlight advantages and disadvantages of each genetic system. We cover methods ranging from simple "twin-spot" analysis to more sophisticated systems of multicolor labeling.
Transgender and intersex athlete inclusion and exclusion from single-sex sports is an area of ongoing conversation and change. This article discusses the separation of male and female athletes, ...looking at the scientific reasoning, the Australian legislation, Australian case law and sport-specific policies. The role of sports' policies and case examples for transgender and intersex athletes are investigated along with the concepts of discrimination and legality. The article concludes that policies and regulations can be discriminatory while still being lawful if they meet relevant exceptions - as outlined by legislation and set out by courts. More research is required in the area of the potential advantage that transgender and intersex athletes may have in both individual and team single-sex sports before definitive statements regarding inclusion or exclusion can be made.
An understanding of how animal size is controlled requires knowledge of how positive and negative growth regulatory signals are balanced and integrated within cells. Here we demonstrate that the ...activities of the conserved growth-promoting transcription factor Myc and the tumor-suppressing Hippo pathway are codependent during growth of Drosophila imaginal discs. We find that Yorkie (Yki), the Drosophila homolog of the Hippo pathway transducer, Yap, regulates the transcription of Myc, and that Myc functions as a critical cellular growth effector of the pathway. We demonstrate that in turn, Myc regulates the expression of Yki as a function of its own cellular level, such that high levels of Myc repress Yki expression through both transcriptional and posttranscriptional mechanisms. We propose that the codependent regulatory relationship functionally coordinates the cellular activities of Yki and Myc and provides a mechanism of growth control that regulates organ size and has broad implications for cancer.
► In fly wing discs, the transcriptional coactivator Yki/YAP induces Myc expression ► Myc is a critical growth effector downstream of the Hippo/Yki pathway ► Myc feeds back on Yki: high levels of Myc repress Yki expression ► Myc and Yki activities are coupled to coordinate tissue growth
In growing tissues, cell fitness disparities can provoke interactions that promote stronger cells at the expense of the weaker in a process called cell competition. The mechanistic definition of cell ...fitness is not understood, nor is it understood how fitness differences are recognized. Drosophila cells with extra Myc activity acquire “supercompetitor” status upon confrontation with wild-type (WT) cells, prompting the latter’s elimination via apoptosis. Here we show that such confrontation enhances glycolytic flux in Myc cells and promotes their fitness and proliferation in a p53-dependent manner. Whereas p53 loss in noncompeting Myc cells is inconsequential, its loss impairs metabolism, reduces viability, and prevents the killing activity of Myc supercompetitor cells. We propose that p53 acts as a general sensor of competitive confrontation to enhance the fitness of the “winner” population. Our findings suggest that the initial confrontation between precancerous and WT cells could enhance cancer cell fitness and promote tumor progression.
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•Supercompetitor status of Myc cells enhances metabolism and reproductive success•Confrontation between Myc-expressing cells and WT cells requires p53 as a sensor•Without p53, Myc supercompetitor cells do not trigger elimination of nearby WT cells•Precancerous cells in healthy tissues may initially require p53 for survival
Extra Myc activity in Drosophila cells promotes “supercompetitor” status of these cells at the expense of weaker cells in mosaic tissues. Here, de la Cova et al. show that p53 promotes and supports the functional transition of Myc-expressing cells into super-competitors. Their findings have implications in understanding cancer cell fitness and tumor formation.
The immunology of food allergy Johnston, Laura K; Chien, Karen B; Bryce, Paul J
The Journal of immunology (1950),
2014-Mar-15, 2014-03-15, 20140315, Letnik:
192, Številka:
6
Journal Article
Recenzirano
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Food allergies represent an increasingly prevalent human health problem, and therapeutic options remain limited, with avoidance being mainstay, despite its adverse effects on quality of life. A ...better understanding of the key immunological mechanisms involved in such responses likely will be vital for development of new therapies. This review outlines the current understanding of how the immune system is thought to contribute to prevention or development of food allergies. Drawing from animal studies, as well as clinical data when available, the importance of oral tolerance in sustaining immunological nonresponsiveness to food Ags, our current understanding of why oral tolerance may fail and sensitization may occur, and the knowledge of pathways that may lead to anaphylaxis and food allergy-associated responses are addressed.
The
let-7 and
lin-4 microRNAs belong to a class of temporally expressed, noncoding regulatory RNAs that function as heterochronic switch genes in the nematode
C. elegans. Heterochronic genes control ...the relative timing of events during development and are considered a major force in the rapid evolution of new morphologies.
let-7 is highly conserved and in
Drosophila is temporally coregulated with the
lin-4 homolog,
miR-125. Little is known, however, about their requirement outside the nematode or whether they universally control the timing of developmental processes.
We report the generation of a
Drosophila mutant that lacks
let-7 and
miR-125 activities and that leads to a pleiotropic phenotype arising during metamorphosis. We focus on two defects and demonstrate that loss of
let-7 and
miR-125 results in temporal delays in two distinct metamorphic processes: the terminal cell-cycle exit in the wing and maturation of neuromuscular junctions (NMJs) at adult abdominal muscles. We identify the
abrupt (
ab) gene, encoding a nuclear protein, as a bona fide
let-7 target and provide evidence that
let-7 governs the maturation rate of abdominal NMJs during metamorphosis by regulating
ab expression.
Drosophila Iet-7 and
miR-125 mutants exhibit temporal misregulation of specific metamorphic processes. As in
C. elegans,
Drosophila let-7 is both necessary and sufficient for the appropriate timing of a specific cell-cycle exit, indicating that its function as a heterochronic microRNA is conserved. The
ab gene is a target of
let-7, and its repression in muscle is essential for the timing of NMJ maturation during metamorphosis. Our results suggest that
let-7 and
miR-125 serve as conserved regulators of events necessary for the transition from juvenile to adult life stages.
Macrophages are key orchestrators of the inflammatory and repair responses in the lung, and the diversity of their function is indicated by their polarized states and distinct subpopulations and ...localization in the lung. Here, we characterized the pulmonary macrophage populations in the interstitial and alveolar compartments during the induction and resolution of acute lung injury induced by Pseudomonas aeruginosa infection. We identified macrophage subpopulations and polarity according to FACS analysis of cell surface protein markers, combined with cell sorting for gene expression using real-time PCR. With these techniques, we validated a novel, alternatively activated (M2) marker (transferrin receptor), and we described three interstitial and alveolar macrophage subpopulations in the lung whose distribution and functional state evolved from the induction to resolution phases of lung injury. Together, these findings indicate the presence and evolution of distinct macrophage subsets in the lung that serve specific niches in regulating the inflammatory response and its resolution. Alterations in the balance and function of these subpopulations could lead to nonresolving acute lung injury.
Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis, and eczema. Whereas IL-5 is crucial for supporting mature eosinophils (EoMs), the signals ...that support earlier eosinophil lineage events are less defined. The IL-33R, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in peripheral tissues. Recently, ST2 expression was described on hematopoietic progenitor subsets, where its function remains controversial. Our findings demonstrate that IL-33 is required for basal eosinophil homeostasis, because both IL-33- and ST2-deficient mice exhibited diminished peripheral blood eosinophil numbers at baseline. Exogenous IL-33 administration increased EoMs in both the bone marrow and the periphery in wild-type and IL-33-deficient, but not ST2-deficient, mice. Systemic IL-5 was also increased under this treatment, and blocking IL-5 with a neutralizing Ab ablated the IL-33-induced EoM expansion. The homeostatic hypereosinophilia seen in IL-5-transgenic mice was significantly lower with ST2 deficiency despite similar elevations in systemic IL-5. Finally, in vitro treatment of bone marrow cells with IL-33, but not IL-5, led to specific early expansion of IL-5Rα-expressing precursor cells. In summary, our findings establish a basal defect in eosinophilopoiesis in IL-33- and ST2-deficient mice and a mechanism whereby IL-33 supports EoMs by driving both systemic IL-5 production and the expansion of IL-5Rα-expressing precursor cells.
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