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Nature Reviews. Molecular Cell Biology Aug 2022Epithelial cells are the most common cell type in all animals, forming the sheets and tubes that compose most organs and tissues. Apical-basal polarity is essential for... (Review)
Review
Epithelial cells are the most common cell type in all animals, forming the sheets and tubes that compose most organs and tissues. Apical-basal polarity is essential for epithelial cell form and function, as it determines the localization of the adhesion molecules that hold the cells together laterally and the occluding junctions that act as barriers to paracellular diffusion. Polarity must also target the secretion of specific cargoes to the apical, lateral or basal membranes and organize the cytoskeleton and internal architecture of the cell. Apical-basal polarity in many cells is established by conserved polarity factors that define the apical (Crumbs, Stardust/PALS1, aPKC, PAR-6 and CDC42), junctional (PAR-3) and lateral (Scribble, DLG, LGL, Yurt and RhoGAP19D) domains, although recent evidence indicates that not all epithelia polarize by the same mechanism. Research has begun to reveal the dynamic interactions between polarity factors and how they contribute to polarity establishment and maintenance. Elucidating these mechanisms is essential to better understand the roles of apical-basal polarity in morphogenesis and how defects in polarity contribute to diseases such as cancer.
Topics: Animals; Cell Polarity; Drosophila Proteins; Epithelial Cells; Epithelium; Morphogenesis
PubMed: 35440694
DOI: 10.1038/s41580-022-00465-y -
Science (New York, N.Y.) May 2020Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have... (Review)
Review
Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have been classically assumed to have broad-spectrum activity and simple kinetics, but recent evidence suggests an unexpected degree of specificity and a high capacity for synergies. Deeper evaluation of the molecular evolution and population genetics of AMP genes reveals more evidence for adaptive maintenance of polymorphism in AMP genes than has previously been appreciated, as well as adaptive loss of AMP activity. AMPs exhibit pharmacodynamic properties that reduce the evolution of resistance in target microbes, and AMPs may synergize with one another and with conventional antibiotics. Both of these properties make AMPs attractive for translational applications. However, if AMPs are to be used clinically, it is crucial to understand their natural biology in order to lessen the risk of collateral harm and avoid the crisis of resistance now facing conventional antibiotics.
Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Drosophila Proteins; Drug Resistance, Bacterial; Drug Synergism; Evolution, Molecular; Humans; Polymorphism, Genetic; Translational Research, Biomedical
PubMed: 32355003
DOI: 10.1126/science.aau5480 -
Molecular Cell May 2023The prevailing view of metazoan gene regulation is that transcription is facilitated through the formation of static activator complexes at distal regulatory regions....
The prevailing view of metazoan gene regulation is that transcription is facilitated through the formation of static activator complexes at distal regulatory regions. Here, we employed quantitative single-cell live-imaging and computational analysis to provide evidence that the dynamic assembly and disassembly process of transcription factor (TF) clusters at enhancers is a major source of transcriptional bursting in developing Drosophila embryos. We further show that the regulatory connectivity between TF clustering and burst induction is highly regulated through intrinsically disordered regions (IDRs). Addition of a poly-glutamine tract to the maternal morphogen Bicoid demonstrated that extended IDR length leads to ectopic TF clustering and burst induction from its endogenous target genes, resulting in defects in body segmentation during embryogenesis. Moreover, we successfully visualized the presence of "shared" TF clusters during the co-activation of two distant genes, which provides a concrete molecular explanation for the newly proposed "topological operon" hypothesis in metazoan gene regulation.
Topics: Animals; Transcription Factors; Drosophila Proteins; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Drosophila
PubMed: 37207625
DOI: 10.1016/j.molcel.2023.04.018 -
Trends in Neurosciences Apr 2021Mechanosensation in Drosophila relies on sensory neurons transducing mechanical stimuli into ionic currents. The molecular mechanisms of this transduction are in the... (Review)
Review
Mechanosensation in Drosophila relies on sensory neurons transducing mechanical stimuli into ionic currents. The molecular mechanisms of this transduction are in the process of being revealed. Transduction relies on mechanogated ion channels that are activated by membrane stretch or the tension of force-conveying tethers. NOMPC (no-mechanoreceptor potential C) and DmPiezo were put forward as bona fide mechanoelectrical transduction (MET) channels, providing insights into MET channel architecture and the structural basis of mechanogating. Various additional channels were implicated in Drosophila mechanosensory neuron functions, and parallels between fly and vertebrate mechanotransduction were delineated. Collectively, these advances put forward Drosophila mechanosensory neurons as cellular paradigms for mechanotransduction and mechanogated ion channel function in the context of proprio- and nociception as well as the detection of substrate vibrations, touch, gravity, and sound.
Topics: Animals; Drosophila; Drosophila Proteins; Drosophila melanogaster; Mechanotransduction, Cellular; Sensory Receptor Cells; Transient Receptor Potential Channels
PubMed: 33257000
DOI: 10.1016/j.tins.2020.11.001 -
Nature Neuroscience Apr 2024Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of...
Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.
Topics: Animals; Neuroglia; Drosophila Proteins; Neurons; Drosophila; Homeostasis; Sleep; Lipids
PubMed: 38360946
DOI: 10.1038/s41593-023-01568-1 -
Fly 2020Post-translational modifications (PTMs) are critical drivers and attenuators for proteins that regulate immune signalling cascades in host defence. In this review, we... (Review)
Review
Post-translational modifications (PTMs) are critical drivers and attenuators for proteins that regulate immune signalling cascades in host defence. In this review, we explore functional roles for one such PTM, the small ubiquitin-like modifier (SUMO). Very few of the SUMO conjugation targets identified by proteomic studies have been validated in terms of their roles in host defence. Here, we compare and contrast potential SUMO substrate proteins in immune signalling for flies and mammals, with an emphasis on NFκB pathways. We discuss, using the few mechanistic studies that exist for validated targets, the effect of SUMO conjugation on signalling and also explore current molecular models that explain regulation by SUMO. We also discuss in detail roles of evolutionary conservation of mechanisms, SUMO interaction motifs, crosstalk of SUMO with other PTMs, emerging concepts such as group SUMOylation and finally, the potentially transforming roles for genome-editing technologies in studying the effect of PTMs.
Topics: Animals; Drosophila Proteins; Drosophila melanogaster; Gene Expression Regulation; Protein Processing, Post-Translational; Signal Transduction; Small Ubiquitin-Related Modifier Proteins
PubMed: 32777975
DOI: 10.1080/19336934.2020.1808402 -
The Journal of Comparative Neurology Oct 2023Insects from high latitudes spend the winter in a state of overwintering diapause, which is characterized by arrested reproduction, reduced food intake and metabolism,...
Insects from high latitudes spend the winter in a state of overwintering diapause, which is characterized by arrested reproduction, reduced food intake and metabolism, and increased life span. The main trigger to enter diapause is the decreasing day length in summer-autumn. It is thus assumed that the circadian clock acts as an internal sensor for measuring photoperiod and orchestrates appropriate seasonal changes in physiology and metabolism through various neurohormones. However, little is known about the neuronal organization of the circadian clock network and the neurosecretory system that controls diapause in high-latitude insects. We addressed this here by mapping the expression of clock proteins and neuropeptides/neurohormones in the high-latitude fly Drosophila littoralis. We found that the principal organization of both systems is similar to that in Drosophila melanogaster, but with some striking differences in neuropeptide expression levels and patterns. The small ventrolateral clock neurons that express pigment-dispersing factor (PDF) and short neuropeptide F (sNPF) and are most important for robust circadian rhythmicity in D. melanogaster virtually lack PDF and sNPF expression in D. littoralis. In contrast, dorsolateral clock neurons that express ion transport peptide in D. melanogaster additionally express allatostatin-C and appear suited to transfer day-length information to the neurosecretory system of D. littoralis. The lateral neurosecretory cells of D. littoralis contain more neuropeptides than D. melanogaster. Among them, the cells that coexpress corazonin, PDF, and diuretic hormone 44 appear most suited to control diapause. Our work sets the stage to investigate the roles of these diverse neuropeptides in regulating insect diapause.
Topics: Animals; Drosophila; Drosophila melanogaster; CLOCK Proteins; Circadian Rhythm; Diapause; Circadian Clocks; Neuropeptides; Drosophila Proteins
PubMed: 37493077
DOI: 10.1002/cne.25522 -
Genetics Sep 2020Key discoveries in have shaped our understanding of cellular "enhancers." With a special focus on the fly, this chapter surveys properties of these adaptable... (Review)
Review
Key discoveries in have shaped our understanding of cellular "enhancers." With a special focus on the fly, this chapter surveys properties of these adaptable -regulatory elements, whose actions are critical for the complex spatial/temporal transcriptional regulation of gene expression in metazoa. The powerful combination of genetics, molecular biology, and genomics available in has provided an arena in which the developmental role of enhancers can be explored. Enhancers are characterized by diverse low- or high-throughput assays, which are challenging to interpret, as not all of these methods of identifying enhancers produce concordant results. As a model metazoan, the fly offers important advantages to comprehensive analysis of the central functions that enhancers play in gene expression, and their critical role in mediating the production of phenotypes from genotype and environmental inputs. A major challenge moving forward will be obtaining a quantitative understanding of how these -regulatory elements operate in development and disease.
Topics: Animals; Drosophila Proteins; Drosophila melanogaster; Enhancer Elements, Genetic; Genetic Techniques; Transcription Factors; Transcriptional Activation
PubMed: 32878914
DOI: 10.1534/genetics.120.301370 -
Current Topics in Developmental Biology 2022The molecular complexes underlying planar cell polarity (PCP) were first identified in Drosophila through analysis of mutant phenotypes in the adult cuticle and the... (Review)
Review
The molecular complexes underlying planar cell polarity (PCP) were first identified in Drosophila through analysis of mutant phenotypes in the adult cuticle and the orientation of associated polarized protrusions such as wing hairs and sensory bristles. The same molecules are conserved in vertebrates and are required for the localization of polarized protrusions such as primary or sensory cilia and the orientation of hair follicles. Not only is PCP signaling required to align cellular structures across a tissue, it is also required to coordinate movement during embryonic development and adult homeostasis. PCP signaling allows cells to interpret positional cues within a tissue to move in the appropriate direction and to coordinate this movement with their neighbors. In this review we outline the molecular basis of the core Wnt-Frizzled/PCP pathway, and describe how this signaling orchestrates collective motility in Drosophila and vertebrates. Here we cover the paradigms of ommatidial rotation and border cell migration in Drosophila, and convergent extension in vertebrates. The downstream cell biological processes that underlie polarized motility include cytoskeletal reorganization, and adherens junctional and extracellular matrix remodeling. We discuss the contributions of these processes in the respective cell motility contexts. Finally, we address examples of individual cell motility guided by PCP factors during nervous system development and in cancer disease contexts.
Topics: Animals; Cell Movement; Cell Polarity; Drosophila; Drosophila Proteins; Vertebrates; Wnt Signaling Pathway
PubMed: 35817505
DOI: 10.1016/bs.ctdb.2022.03.006 -
Current Opinion in Neurobiology Apr 2022The representation of contextual information peripheral to a salient stimulus is central to an animal's ability to correctly interpret and flexibly respond to that... (Review)
Review
The representation of contextual information peripheral to a salient stimulus is central to an animal's ability to correctly interpret and flexibly respond to that stimulus. While the computations and circuits underlying the context-dependent modulation of stimulus-response pairings have typically been studied in vertebrates, the genetic tractability, numeric simplification, and well-characterized connectivity patterns of the Drosophila melanogaster brain have facilitated circuit-level insights into contextual processing. Recent studies in flies reveal the neuronal mechanisms that create flexible context-dependent behavioral responses to sensory events in conditions of predation threat, feeding regulation, and social interaction.
Topics: Animals; Behavior, Animal; Brain; Drosophila; Drosophila Proteins; Drosophila melanogaster
PubMed: 35286864
DOI: 10.1016/j.conb.2022.02.003