RESUMO
We have produced gene expression profiles of all 302 neurons of the C. elegans nervous system that match the single-cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses distinct codes of â¼23 neuropeptide genes and â¼36 neuropeptide receptors, delineating a complex and expansive "wireless" signaling network. To demonstrate the utility of this comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression and (2) reveal adhesion proteins with potential roles in process placement and synaptic specificity. Our expression data are available at https://cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity, and function throughout the C. elegans nervous system.
Assuntos
Caenorhabditis elegans/metabolismo , Sistema Nervoso/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Corantes Fluorescentes/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Larva/metabolismo , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Motivos de Nucleotídeos/genética , RNA-Seq , Sequências Reguladoras de Ácido Nucleico/genética , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
Long-term subcellular intravital imaging in mammals is vital to study diverse intercellular behaviors and organelle functions during native physiological processes. However, optical heterogeneity, tissue opacity, and phototoxicity pose great challenges. Here, we propose a computational imaging framework, termed digital adaptive optics scanning light-field mutual iterative tomography (DAOSLIMIT), featuring high-speed, high-resolution 3D imaging, tiled wavefront correction, and low phototoxicity with a compact system. By tomographic imaging of the entire volume simultaneously, we obtained volumetric imaging across 225 × 225 × 16 µm3, with a resolution of up to 220 nm laterally and 400 nm axially, at the millisecond scale, over hundreds of thousands of time points. To establish the capabilities, we investigated large-scale cell migration and neural activities in different species and observed various subcellular dynamics in mammals during neutrophil migration and tumor cell circulation.
Assuntos
Algoritmos , Imageamento Tridimensional , Óptica e Fotônica , Tomografia , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular , Drosophila , Células HeLa , Humanos , Larva/fisiologia , Fígado/diagnóstico por imagem , Masculino , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Ratos Sprague-Dawley , Razão Sinal-Ruído , Frações Subcelulares/fisiologia , Fatores de Tempo , Peixe-ZebraRESUMO
Goal-directed behavior requires the interaction of multiple brain regions. How these regions and their interactions with brain-wide activity drive action selection is less understood. We have investigated this question by combining whole-brain volumetric calcium imaging using light-field microscopy and an operant-conditioning task in larval zebrafish. We find global, recurring dynamics of brain states to exhibit pre-motor bifurcations toward mutually exclusive decision outcomes. These dynamics arise from a distributed network displaying trial-by-trial functional connectivity changes, especially between cerebellum and habenula, which correlate with decision outcome. Within this network the cerebellum shows particularly strong and predictive pre-motor activity (>10 s before movement initiation), mainly within the granule cells. Turn directions are determined by the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the rate of bi-hemispheric population ramping quantitatively predicts decision time on the trial-by-trial level. Our results highlight a cognitive role of the cerebellum and its importance in motor planning.
Assuntos
Cerebelo/fisiologia , Tomada de Decisões/fisiologia , Tempo de Reação/fisiologia , Peixe-Zebra/fisiologia , Animais , Comportamento Animal/fisiologia , Mapeamento Encefálico/métodos , Cérebro/fisiologia , Cognição/fisiologia , Condicionamento Operante/fisiologia , Objetivos , Habenula/fisiologia , Temperatura Alta , Larva/fisiologia , Atividade Motora/fisiologia , Movimento , Neurônios/fisiologia , Desempenho Psicomotor/fisiologia , Rombencéfalo/fisiologiaRESUMO
The specific patterns and functional properties of electrical synapses of a nervous system are defined by the neuron-specific complement of electrical synapse constituents. We systematically examined the molecular composition of the electrical connectome of the nematode C. elegans through a genome- and nervous-system-wide analysis of the expression patterns of the invertebrate electrical synapse constituents, the innexins. We observe highly complex combinatorial expression patterns throughout the nervous system and found that these patterns change in a strikingly neuron-type-specific manner throughout the nervous system when animals enter an insulin-controlled diapause arrest stage under harsh environmental conditions, the dauer stage. By analyzing several individual synapses, we demonstrate that dauer-specific electrical synapse remodeling is responsible for specific aspects of the altered locomotory and chemosensory behavior of dauers. We describe an intersectional gene regulatory mechanism involving terminal selector and FoxO transcription factors mediating dynamic innexin expression plasticity in a neuron-type- and environment-specific manner.
Assuntos
Caenorhabditis elegans/fisiologia , Sinapses Elétricas/metabolismo , Plasticidade Neuronal/fisiologia , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Conectoma/métodos , Regulação da Expressão Gênica no Desenvolvimento/genética , Larva/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Prolonged behavioral challenges can cause animals to switch from active to passive coping strategies to manage effort-expenditure during stress; such normally adaptive behavioral state transitions can become maladaptive in psychiatric disorders such as depression. The underlying neuronal dynamics and brainwide interactions important for passive coping have remained unclear. Here, we develop a paradigm to study these behavioral state transitions at cellular-resolution across the entire vertebrate brain. Using brainwide imaging in zebrafish, we observed that the transition to passive coping is manifested by progressive activation of neurons in the ventral (lateral) habenula. Activation of these ventral-habenula neurons suppressed downstream neurons in the serotonergic raphe nucleus and caused behavioral passivity, whereas inhibition of these neurons prevented passivity. Data-driven recurrent neural network modeling pointed to altered intra-habenula interactions as a contributory mechanism. These results demonstrate ongoing encoding of experience features in the habenula, which guides recruitment of downstream networks and imposes a passive coping behavioral strategy.
Assuntos
Adaptação Psicológica/fisiologia , Habenula/fisiologia , Animais , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Habenula/metabolismo , Larva , Vias Neurais/metabolismo , Neurônios/metabolismo , Núcleos da Rafe/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina , Estresse Fisiológico/fisiologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismoRESUMO
When a behavior repeatedly fails to achieve its goal, animals often give up and become passive, which can be strategic for preserving energy or regrouping between attempts. It is unknown how the brain identifies behavioral failures and mediates this behavioral-state switch. In larval zebrafish swimming in virtual reality, visual feedback can be withheld so that swim attempts fail to trigger expected visual flow. After tens of seconds of such motor futility, animals became passive for similar durations. Whole-brain calcium imaging revealed noradrenergic neurons that responded specifically to failed swim attempts and radial astrocytes whose calcium levels accumulated with increasing numbers of failed attempts. Using cell ablation and optogenetic or chemogenetic activation, we found that noradrenergic neurons progressively activated brainstem radial astrocytes, which then suppressed swimming. Thus, radial astrocytes perform a computation critical for behavior: they accumulate evidence that current actions are ineffective and consequently drive changes in behavioral states. VIDEO ABSTRACT.
Assuntos
Astrócitos/metabolismo , Comportamento Animal/fisiologia , Larva/fisiologia , Peixe-Zebra/fisiologia , Neurônios Adrenérgicos/metabolismo , Animais , Animais Geneticamente Modificados/fisiologia , Astrócitos/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Mapeamento Encefálico , Cálcio/metabolismo , Comunicação Celular/fisiologia , Retroalimentação Sensorial/fisiologia , Neurônios GABAérgicos/metabolismo , Potenciais da Membrana/fisiologia , Optogenética , Natação/fisiologiaRESUMO
The assembly of phase-separated structures is thought to play an important role in development and disease, but little is known about the regulation and function of phase separation under physiological conditions. We showed that during C. elegans embryogenesis, PGL granules assemble via liquid-liquid phase separation (LLPS), and their size and biophysical properties determine their susceptibility to autophagic degradation. The receptor SEPA-1 promotes LLPS of PGL-1/-3, while the scaffold protein EPG-2 controls the size of PGL-1/-3 compartments and converts them into less dynamic gel-like structures. Under heat-stress conditions, mTORC1-mediated phosphorylation of PGL-1/-3 is elevated and PGL-1/-3 undergo accelerated phase separation, forming PGL granules that are resistant to autophagic degradation. Significantly, accumulation of PGL granules is an adaptive response to maintain embryonic viability during heat stress. We revealed that mTORC1-mediated LLPS of PGL-1/-3 acts as a switch-like stress sensor, coupling phase separation to autophagic degradation and adaptation to stress during development.
Assuntos
Autofagia , Proteínas de Caenorhabditis elegans/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Animais , Arginina/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário , Larva/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Metilação , Mutagênese Sítio-Dirigida , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , TemperaturaRESUMO
Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.
Assuntos
Comportamento Animal , Encéfalo/citologia , Encéfalo/fisiologia , Neurônios/citologia , Animais , Mapeamento Encefálico , Larva/citologia , Larva/fisiologia , Camundongos , Vias Neurais , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/fisiologiaRESUMO
Autophagy degrades cytoplasmic components and is important for development and human health. Although autophagy is known to be influenced by systemic intercellular signals, the proteins that control autophagy are largely thought to function within individual cells. Here, we report that Drosophila macroglobulin complement-related (Mcr), a complement ortholog, plays an essential role during developmental cell death and inflammation by influencing autophagy in neighboring cells. This function of Mcr involves the immune receptor Draper, suggesting a relationship between autophagy and the control of inflammation. Interestingly, Mcr function in epithelial cells is required for macrophage autophagy and migration to epithelial wounds, a Draper-dependent process. This study reveals, unexpectedly, that complement-related from one cell regulates autophagy in neighboring cells via an ancient immune signaling program.
Assuntos
Autofagia , Proteínas do Sistema Complemento/imunologia , Drosophila melanogaster/crescimento & desenvolvimento , Animais , Citocinas , Proteínas de Drosophila , Drosophila melanogaster/citologia , Drosophila melanogaster/imunologia , Inflamação/imunologia , Larva/crescimento & desenvolvimento , Larva/imunologia , Macrófagos/imunologia , Glândulas Salivares/citologia , Glândulas Salivares/crescimento & desenvolvimento , Glândulas Salivares/metabolismo , SerpinasRESUMO
Animals generate complex patterns of behavior across development that may be shared or unique to individuals. Here, we examine the contributions of developmental programs and individual variation to behavior by monitoring single Caenorhabditis elegans nematodes over their complete developmental trajectories and quantifying their behavior at high spatiotemporal resolution. These measurements reveal reproducible trajectories of spontaneous foraging behaviors that are stereotyped within and between developmental stages. Dopamine, serotonin, the neuropeptide receptor NPR-1, and the TGF-ß peptide DAF-7 each have stage-specific effects on behavioral trajectories, implying the existence of a modular temporal program controlled by neuromodulators. In addition, a fraction of individuals within isogenic populations raised in controlled environments have consistent, non-genetic behavioral biases that persist across development. Several neuromodulatory systems increase or decrease the degree of non-genetic individuality to shape sustained patterns of behavior across the population.
Assuntos
Variação Biológica Individual , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Neuropeptídeos/metabolismo , Animais , Comportamento Animal , Dopamina/metabolismo , Regulação da Expressão Gênica , Larva/fisiologia , Neuroimagem/instrumentação , Neuroimagem/métodos , Neuropeptídeos/genética , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismoRESUMO
We examined the evolutionary history of leading multidrug resistant hospital pathogens, the enterococci, to their origin hundreds of millions of years ago. Our goal was to understand why, among the vast diversity of gut flora, enterococci are so well adapted to the modern hospital environment. Molecular clock estimation, together with analysis of their environmental distribution, phenotypic diversity, and concordance with host fossil records, place the origins of the enterococci around the time of animal terrestrialization, 425-500 mya. Speciation appears to parallel the diversification of hosts, including the rapid emergence of new enterococcal species following the End Permian Extinction. Major drivers of speciation include changing carbohydrate availability in the host gut. Life on land would have selected for the precise traits that now allow pathogenic enterococci to survive desiccation, starvation, and disinfection in the modern hospital, foreordaining their emergence as leading hospital pathogens.
Assuntos
Evolução Biológica , Enterococcus/genética , Animais , Doenças Transmissíveis Emergentes/microbiologia , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana , Enterococcus/classificação , Enterococcus/citologia , Enterococcus/efeitos dos fármacos , Especiação Genética , Interações Hospedeiro-Patógeno , Larva/microbiologia , Mariposas/crescimento & desenvolvimento , Mariposas/microbiologia , Filogenia , RNA Ribossômico 16S/genéticaRESUMO
Mycobacterium leprae causes leprosy and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interaction of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum-expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy.
Assuntos
Antígenos de Bactérias/metabolismo , Modelos Animais de Doenças , Glicolipídeos/metabolismo , Hanseníase/microbiologia , Hanseníase/patologia , Macrófagos/imunologia , Mycobacterium leprae/fisiologia , Animais , Axônios/metabolismo , Axônios/patologia , Doenças Desmielinizantes , Larva/crescimento & desenvolvimento , Hanseníase/imunologia , Mycobacterium marinum/metabolismo , Bainha de Mielina/química , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Neuroglia/metabolismo , Neuroglia/patologia , Óxido Nítrico/metabolismo , Peixe-ZebraRESUMO
Monomethylation of lysine 20 of histone H4 (H4K20me1) is catalyzed by Set8 and thought to play important roles in many aspects of genome function that are mediated by H4K20me binding proteins. We interrogated this model in a developing animal by comparing in parallel the transcriptomes of Set8 null , H4 K20R/A , and l(3)mbt mutant Drosophila melanogaster We found that the gene expression profiles of H4 K20A and H4 K20R larvae are markedly different than Set8 null larvae despite similar reductions in H4K20me1. Set8 null mutant cells have a severely disrupted transcriptome and fail to proliferate in vivo, but these phenotypes are not recapitulated by mutation of H4 K20 , indicating that the developmental defects of Set8 null animals are largely due to H4K20me1-independent effects on gene expression. Furthermore, the H4K20me1 binding protein L(3)mbt is recruited to the transcription start sites of most genes independently of H4K20me even though genes bound by L(3)mbt have high levels of H4K20me1. Moreover, both Set8 and L(3)mbt bind to purified H4K20R nucleosomes in vitro. We conclude that gene expression changes in Set8 null and H4 K20 mutants cannot be explained by loss of H4K20me1 or L(3)mbt binding to chromatin and therefore that H4K20me1 does not play a large role in gene expression.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Histona-Lisina N-Metiltransferase , Histonas , Lisina , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Histonas/metabolismo , Histonas/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Metilação , Lisina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Mutação , Transcriptoma/genética , Larva/genética , Larva/metabolismo , Larva/crescimento & desenvolvimentoRESUMO
The goal of comparative developmental biology is identifying mechanistic differences in embryonic development between different taxa and how these evolutionary changes have led to morphological and organizational differences in adult body plans. Much of this work has focused on direct-developing species in which the adult forms straight from the embryo and embryonic modifications have direct effects on the adult. However, most animal lineages are defined by indirect development, in which the embryo gives rise to a larval body plan and the adult forms by transformation of the larva. Historically, much of our understanding of complex life cycles is viewed through the lenses of ecology and zoology. In this review, we discuss the importance of establishing developmental rather than morphological or ecological criteria for defining developmental mode and explicitly considering the evolutionary implications of incorporating complex life cycles into broad developmental comparisons of embryos across metazoans.
Assuntos
Evolução Biológica , Estágios do Ciclo de Vida , Animais , Larva , Desenvolvimento Embrionário/genética , Biologia do DesenvolvimentoRESUMO
Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.
Assuntos
Inflamação/imunologia , Pulmão/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/imunologia , Animais , Inflamação/genética , Inflamação/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Larva/imunologia , Larva/fisiologia , Pulmão/metabolismo , Pulmão/patologia , Ativação de Macrófagos/genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/parasitologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mucina-5B/genética , Mucina-5B/imunologia , Mucina-5B/metabolismo , Nippostrongylus/imunologia , Nippostrongylus/fisiologia , Proteína D Associada a Surfactante Pulmonar/genética , Proteína D Associada a Surfactante Pulmonar/imunologia , Proteína D Associada a Surfactante Pulmonar/metabolismo , Infecções por Strongylida/genética , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologiaRESUMO
Even a simple sensory stimulus can elicit distinct innate behaviors and sequences. During sensorimotor decisions, competitive interactions among neurons that promote distinct behaviors must ensure the selection and maintenance of one behavior, while suppressing others. The circuit implementation of these competitive interactions is still an open question. By combining comprehensive electron microscopy reconstruction of inhibitory interneuron networks, modeling, electrophysiology, and behavioral studies, we determined the circuit mechanisms that contribute to the Drosophila larval sensorimotor decision to startle, explore, or perform a sequence of the two in response to a mechanosensory stimulus. Together, these studies reveal that, early in sensory processing, (1) reciprocally connected feedforward inhibitory interneurons implement behavioral choice, (2) local feedback disinhibition provides positive feedback that consolidates and maintains the chosen behavior, and (3) lateral disinhibition promotes sequence transitions. The combination of these interconnected circuit motifs can implement both behavior selection and the serial organization of behaviors into a sequence.
Assuntos
Comportamento de Escolha/fisiologia , Drosophila melanogaster/fisiologia , Retroalimentação Sensorial/fisiologia , Mecanotransdução Celular/fisiologia , Células de Renshaw/fisiologia , Animais , Larva/fisiologia , OptogenéticaRESUMO
To execute accurate movements, animals must continuously adapt their behavior to changes in their bodies and environments. Animals can learn changes in the relationship between their locomotor commands and the resulting distance moved, then adjust command strength to achieve a desired travel distance. It is largely unknown which circuits implement this form of motor learning, or how. Using whole-brain neuronal imaging and circuit manipulations in larval zebrafish, we discovered that the serotonergic dorsal raphe nucleus (DRN) mediates short-term locomotor learning. Serotonergic DRN neurons respond phasically to swim-induced visual motion, but little to motion that is not self-generated. During prolonged exposure to a given motosensory gain, persistent DRN activity emerges that stores the learned efficacy of motor commands and adapts future locomotor drive for tens of seconds. The DRN's ability to track the effectiveness of motor intent may constitute a computational building block for the broader functions of the serotonergic system. VIDEO ABSTRACT.
Assuntos
Aprendizagem , Modelos Neurológicos , Natação , Peixe-Zebra/fisiologia , Animais , Mapeamento Encefálico , Larva , Optogenética , Núcleos da Rafe/fisiologia , Neurônios Serotoninérgicos/citologia , Neurônios Serotoninérgicos/fisiologia , Processamento EspacialRESUMO
Memories formed early in life are particularly stable and influential, representing privileged experiences that shape enduring behaviors. We show that exposing newly hatched C. elegans to pathogenic bacteria results in persistent aversion to those bacterial odors, whereas adult exposure generates only transient aversive memory. Long-lasting imprinted aversion has a critical period in the first larval stage and is specific to the experienced pathogen. Distinct groups of neurons are required during formation (AIB, RIM) and retrieval (AIY, RIA) of the imprinted memory. RIM synthesizes the neuromodulator tyramine, which is required in the L1 stage for learning. AIY memory retrieval neurons sense tyramine via the SER-2 receptor, which is essential for imprinted, but not for adult-learned, aversion. Odor responses in several neurons, most notably RIA, are altered in imprinted animals. These findings provide insight into neuronal substrates of different forms of memory, and lay a foundation for further understanding of early learning.
Assuntos
Caenorhabditis elegans/fisiologia , Vias Neurais , Neurônios/metabolismo , Animais , Bactérias/química , Comportamento Animal , Caenorhabditis elegans/crescimento & desenvolvimento , Fixação Psicológica Instintiva , Larva/fisiologia , Memória , Receptores de Amina Biogênica/metabolismo , Olfato , Tiramina/metabolismoRESUMO
The Hippo signaling pathway functions through Yorkie to control tissue growth and homeostasis. How this pathway regulates non-developmental processes remains largely unexplored. Here, we report an essential role for Hippo signaling in innate immunity whereby Yorkie directly regulates the transcription of the Drosophila IκB homolog, Cactus, in Toll receptor-mediated antimicrobial response. Loss of Hippo pathway tumor suppressors or activation of Yorkie in fat bodies, the Drosophila immune organ, leads to elevated cactus mRNA levels, decreased expression of antimicrobial peptides, and vulnerability to infection by Gram-positive bacteria. Furthermore, Gram-positive bacteria acutely activate Hippo-Yorkie signaling in fat bodies via the Toll-Myd88-Pelle cascade through Pelle-mediated phosphorylation and degradation of the Cka subunit of the Hippo-inhibitory STRIPAK PP2A complex. Our studies elucidate a Toll-mediated Hippo signaling pathway in antimicrobial response, highlight the importance of regulating IκB/Cactus transcription in innate immunity, and identify Gram-positive bacteria as extracellular stimuli of Hippo signaling under physiological settings.
Assuntos
Drosophila melanogaster/imunologia , Imunidade Inata , Transdução de Sinais , Animais , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Drosophila melanogaster/microbiologia , Escherichia coli/fisiologia , Corpo Adiposo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Larva/metabolismo , Masculino , Pectobacterium carotovorum/fisiologia , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Staphylococcus aureus/fisiologia , Receptores Toll-Like/metabolismoRESUMO
Stem cells reside in specialized microenvironments known as niches. During Drosophila development, glial cells provide a niche that sustains the proliferation of neural stem cells (neuroblasts) during starvation. We now find that the glial cell niche also preserves neuroblast proliferation under conditions of hypoxia and oxidative stress. Lipid droplets that form in niche glia during oxidative stress limit the levels of reactive oxygen species (ROS) and inhibit the oxidation of polyunsaturated fatty acids (PUFAs). These droplets protect glia and also neuroblasts from peroxidation chain reactions that can damage many types of macromolecules. The underlying antioxidant mechanism involves diverting PUFAs, including diet-derived linoleic acid, away from membranes to the core of lipid droplets, where they are less vulnerable to peroxidation. This study reveals an antioxidant role for lipid droplets that could be relevant in many different biological contexts.