The colony-stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microglia in the brain that originates ...from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within 1 week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin-positive cells that then differentiate into microglia.
•Administration of CSF1R inhibitors eliminates 99% of microglia from CNS•Microglia-depleted mice have no deficits in behavior or cognition•Withdrawal of CSF1R inhibitors causes rapid repopulation with new cells•Repopulation occurs from nestin-expressing progenitor cells that become microglia
Elmore et al. show that microglia can be indefinitely eliminated from adult mice with CSF1R inhibitors, allowing direct studies into microglial function. Notably, removal of inhibitors from the microglia-depleted brain unmasks a widespread progenitor cell that rapidly repopulates the CNS.
Immune molecules, including complement proteins C1q and C3, have emerged as critical mediators of synaptic refinement and plasticity. Complement localizes to synapses and refines the developing ...visual system through C3-dependent microglial phagocytosis of synapses. Retinal ganglion cells (RGCs) express C1q, the initiating protein of the classical complement cascade, during retinogeniculate refinement; however, the signals controlling C1q expression and function remain elusive. Previous work implicated an astrocyte-derived factor in regulating neuronal C1q expression. Here we identify retinal transforming growth factor (TGF)-β as a key regulator of neuronal C1q expression and synaptic pruning in the developing visual system. Mice lacking TGF-β receptor II (TGFβRII) in retinal neurons had reduced C1q expression in RGCs and reduced synaptic localization of complement, and phenocopied refinement defects observed in complement-deficient mice, including reduced eye-specific segregation and microglial engulfment of RGC inputs. These data implicate TGF-β in regulating neuronal C1q expression to initiate complement- and microglia-mediated synaptic pruning.
Cells, the basic units of biological structure and function, vary broadly in type and state. Single-cell genomics can characterize cell identity and function, but limitations of ease and scale have ...prevented its broad application. Here we describe Drop-seq, a strategy for quickly profiling thousands of individual cells by separating them into nanoliter-sized aqueous droplets, associating a different barcode with each cell’s RNAs, and sequencing them all together. Drop-seq analyzes mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts’ cell of origin. We analyzed transcriptomes from 44,808 mouse retinal cells and identified 39 transcriptionally distinct cell populations, creating a molecular atlas of gene expression for known retinal cell classes and novel candidate cell subtypes. Drop-seq will accelerate biological discovery by enabling routine transcriptional profiling at single-cell resolution.
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•Drop-seq enables highly parallel analysis of individual cells by RNA-seq•Drop-seq encapsulates cells in nanoliter droplets together with DNA-barcoded beads•Systematic evaluation of Drop-seq library quality using species mixing experiments•Drop-seq analysis of 44,808 cells identifies 39 cell populations in the retina
Capturing single cells along with sets of uniquely barcoded primer beads together in tiny droplets enables large-scale, highly parallel single-cell transcriptomics. Applying this analysis to cells in mouse retinal tissue revealed transcriptionally distinct cell populations along with molecular markers of each type.
The skeletal muscle extracellular matrix (ECM) plays an important role in muscle fiber force transmission, maintenance, and repair. In both injured and diseased states, ECM adapts dramatically, a ...property that has clinical manifestations and alters muscle function. Here we review the structure, composition, and mechanical properties of skeletal muscle ECM; describe the cells that contribute to the maintenance of the ECM; and, finally, overview changes that occur with pathology. New scanning electron micrographs of ECM structure are also presented with hypotheses about ECM structure–function relationships. Detailed structure–function relationships of the ECM have yet to be defined and, as a result, we propose areas for future study. Muscle Nerve 44: 318–331, 2011
Abstract
Background and Objectives
The coronavirus disease 2019 (COVID-19) pandemic has created unique stressors for older people to manage. Informed by the Stress Process Model and the Transactional ...Model of Stress and Coping, we examined the extent to which older people are adhering to physical distancing mandates and the pandemic-related experiences that older people find most challenging.
Research Design and Methods
From May 4 to May 17, 2020, a web-based questionnaire focused on the COVID-19 pandemic was completed by 1,272 people (aged 64 and older) who were part of an ongoing research panel in New Jersey recruited in 2006. Frequencies for endorsement of physical distancing behaviors were tabulated, and open-ended responses to the biggest challenge of the pandemic were systematically coded and classified using content analysis.
Results
More than 70% of participants reported adhering to physical distancing behaviors. Experiences appraised as most difficult by participants fell into 8 domains: Social Relationships, Activity Restrictions, Psychological, Health, Financial, Global Environment, Death, and Home Care. The most frequently appraised challenges were constraints on social interactions (42.4%) and restrictions on activity (30.9%).
Discussion and Implications
In the initial weeks of the pandemic, the majority of older adults reported adhering to COVID-19 physical distancing mandates and identified a range of challenging experiences. Results highlight the factors having the greatest impact on older adults, informing quantitative modeling for testing the impact of the pandemic on health and well-being outcomes, and identifying how intervention efforts may be targeted to maximize the quality of life of older adults.
In a variety of infections, bacteria form multicellular communities which contribute to virulence and antibiotic tolerance. The molecular biology of such communities is actively studied, but our ...understanding of them remains incomplete. In this issue, Şimşek et al have developed and experimentally validated a dynamic model for community formation and revealed general insights into bacterial collective survival during antibiotic exposure.
KR Allison discusses a dynamic model of multicellular “patches” of bacteria upon antibiotic treatment to show beneficial community interactions support their collective survival as reported by Şimşek et al in this issue of
Molecular Systems Biology
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Marine plankton elemental stoichiometric ratios can deviate from the Redfield ratio (106C:16N:1P); here, we examine physiological and biogeochemical mechanisms that lead to the observed variation ...across lineages, regions, and seasons. Many models of ecological stoichiometry blend together acclimative and adaptive responses to environmental conditions. These two pathways can have unique molecular mechanisms and stoichiometric outcomes, and we attempt to disentangle the two processes. We find that interactions between environmental conditions and cellular growth are key to understanding stoichiometric regulation, but the growth rates of most marine plankton populations are poorly constrained. We propose that specific physiological mechanisms have a strong impact on plankton and community stoichiometry in nutrient-rich environments, whereas biogeochemical interactions are important for the stoichiometry of the oligotrophic gyres. Finally, we outline key areas with missing information that is needed to advance understanding of the present and future ecological stoichiometry of ocean plankton.
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility ...complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
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