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Foundations and implications of astrocyte heterogeneity during brain development and disease

TRENDS IN NEUROSCIENCES (2022)

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Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis

Doaa M. Taha et al.

Summary: This study investigates the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis. By using enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations, the study shows that reactive transformation can occur cell-autonomously in ALS astrocytes and there is molecular and functional heterogeneity between different disease-causing mutations.

BRAIN (2022)

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Article Clinical Neurology

Proteomic analysis of human hippocampal subfields provides new insights into the pathogenesis of Alzheimer's disease and the role of glial cells

Yanpan Gao et al.

Summary: This study conducted a comprehensive proteomic analysis of the hippocampal subfields and entorhinal cortex (EC) in Alzheimer's disease (AD). The results revealed differentially expressed proteins (DEPs) associated with astrocytes, oligodendrocytes, and myelin sheath in specific regions. The increase of S100A10-positive astrocytes suggests their protective role through phagocytosis of apoptotic neurons. Additionally, the loss of myelin markers in the EC region highlights the involvement of glial cells in AD pathology.

BRAIN PATHOLOGY (2022)

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Review Neurosciences

Deciphering the functional nano-anatomy of the tripartite synapse using stimulated emission depletion microscopy

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Summary: Studying neuron-astrocyte communication faces challenges in visualizing the tripartite synapse, where STED microscopy offers nanoscale live imaging opportunities. Despite challenges in live-tissue imaging, STED studies have revealed new insights into the structure and function of the tripartite synapse, shedding light on the role of astrocytes in brain physiology and behavior.

GLIA (2022)

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Article Multidisciplinary Sciences

Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aβ pathology

Zoeb Jiwaji et al.

Summary: Alzheimer's disease affects astrocytes, and both A beta and Tau pathology induce changes in astrocytes. A beta mainly influences the expression of AD risk genes, while both pathologies induce age-dependent changes and have overlapping features with astrocytes found in post-mortem AD patients. Both A beta and Tau pathology alter the characteristics of astrocytes, including repression of bioenergetic and translation machinery, induction of inflammation pathways, and expression of protein degradation/proteostasis genes. Astrocyte-specific expression of Nrf2, a protective factor, can recapitulate elements of these astrocyte changes and reduce A beta deposition and phospho-tau accumulation. This Nrf2 expression also improves brain-wide transcriptional deregulation, cellular pathology, neurodegeneration, and behavioral/cognitive deficits.

NATURE COMMUNICATIONS (2022)

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Article Cell Biology

Sex differences in developmental patterns of neocortical astroglia: A mouse translatome database

Gareth M. Rurak et al.

Summary: This study examines the sex differences and developmental changes in cortical astroglial cells. The results reveal two distinct phenotypes of astroglia during early and late development, while sex differences are mainly reflected in gene expression patterns during development.

CELL REPORTS (2022)

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Review Biochemistry & Molecular Biology

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

Shinichi Takahashi et al.

Summary: Oxidative stress and neuroinflammation play important roles in the onset and progression of many neurodegenerative diseases. Parkinson's disease, which is characterized by the loss of dopaminergic neurons leading to dopamine depletion, has different pathogenesis in hereditary and solitary forms. The interactions between dopamine, glial cells, and the presence of neuroinflammation are attracting attention in Parkinson's disease.

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Redefining varicose projection astrocytes in primates

Carmen Falcone et al.

Summary: Varicose projection astrocytes (VP-As) are a specific cell type found only in humans and other apes, localized to layer VI and the superficial white matter of the cortex. Their presence co-occurs with interlaminar astrocytes, and they develop varicosities under specific conditions, suggesting they are not a distinct astrocyte type.

GLIA (2022)

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Article Neurosciences

A closer look at astrocyte morphology: Development, heterogeneity, and plasticity at astrocyte leaflets

Beatriz Torres-Ceja et al.

Summary: Astrocytes are morphologically complex glial cells that play important roles in various functions of the central nervous system. Recent advances in research have revealed the plastic nature of astrocytes, particularly at synapses, and have provided new technologies for studying these cells.

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Neuronal activity drives pathway-specific depolarization of peripheral astrocyte processes

Moritz Armbruster et al.

Summary: This study reveals a novel form of communication between astrocytes and neurons, where neuronal activity induces significant depolarizations in astrocyte processes. These depolarizations are driven by presynaptic potassium efflux and glutamate transporters, and they inhibit astrocyte glutamate clearance, enhancing neuronal activation by glutamate.

NATURE NEUROSCIENCE (2022)

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Article Cell Biology

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical synapse development

Yajun Xie et al.

Summary: Neuron-glia interactions, particularly through the Sonic hedgehog (Shh) pathway, play a crucial role in coordinating synaptic connectivity in the cortex. Shh signaling in cortical astrocytes regulates synaptic development, astrocyte morphology, and excitatory synapse formation, ultimately shaping circuit assembly and function during development. Loss of Shh in layer V neurons affects astrocyte complexity and synaptic coverage, while activation of Shh signaling in astrocytes promotes cortical synapse formation.

CELL REPORTS (2022)

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Review Neurosciences

Astrocytes in the regulation of cerebrovascular functions

Martine Cohen-Salmon et al.

Summary: Astrocytes play a crucial role in regulating the cerebrovascular system by controlling perivascular homeostasis, blood-brain barrier integrity, metabolite transfer, and blood vessel contractility in response to neuronal activity. Although research in this area is still in its early stages, there have been discussions on the role of astrocytes in the cerebrovascular system.

GLIA (2021)

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Review Biology

Astrocytes in Neurodegenerative Diseases: A Perspective from Tauopathy and α-Synucleinopathy

Peng Wang et al.

Summary: Neurodegenerative diseases primarily affect neurons and are characterized by inclusion bodies containing misfolded proteins. Misfolded proteins produced by neurons can be transmitted to other cells, changing their physiological state. Astrocytes are particularly sensitive to these proteotoxic insults, becoming activated and impacting neuronal functions.

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Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis

Joon-Hyuk Lee et al.

Summary: This study demonstrates that astrocytes in the adult hippocampus carry out phagocytosis through MEGF10 to maintain proper synaptic connectivity and plasticity. The findings reveal the crucial role of astrocytes in the activity-dependent elimination of excitatory synapses, highlighting the importance of this astrocytic function in supporting cognitive function.

NATURE (2021)

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Review Developmental Biology

The role of astrocyte-mediated plasticity in neural circuit development and function

Nelson A. Perez-Catalan et al.

Summary: Neural plasticity is crucial for shaping circuit function during nervous system development, and is regulated by astrocytes, the most abundant glial cell type in the human nervous system. Recent technological advancements have highlighted the important role of astrocytes in regulating circuit assembly and function.

NEURAL DEVELOPMENT (2021)

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Article Neurosciences

Light microscopic and heterogeneity analysis of astrocytes in the common marmoset brain

Yorka Munoz et al.

Summary: Astrocytes in the primate brain, particularly in the common marmoset, show molecular and structural heterogeneity across different brain regions, with differences in expression of markers and transporters. This complexity is further demonstrated by variations in astrocyte structure and interactions with blood vessels, microglia, and neurons. The study enhances our understanding of the diverse properties of astrocytes in the primate central nervous system.

JOURNAL OF NEUROSCIENCE RESEARCH (2021)

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Astrocytes mediate the effect of oxytocin in the central amygdala on neuronal activity and affective states in rodents

Jerome Wahis et al.

Summary: This study reveals a morphologically distinct subpopulation of astrocytes expressing OT receptors in the central amygdala of mice and rats, mediating the anxiolytic and positive reinforcement effects of OT. It challenges the traditional belief that OT exclusively acts on neurons, highlighting the essential role of astrocytes in modulating emotional states under normal and chronic pain conditions.

NATURE NEUROSCIENCE (2021)

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Review Neurosciences

Reactive astrocyte nomenclature, definitions, and future directions

Carole Escartin et al.

Summary: The article highlights the challenges and uncertainties surrounding reactive astrocytes, advocating for comprehensive research that includes assessment of multiple molecular and functional parameters, preferably in vivo, along with multivariate statistics and determination of impact on pathological hallmarks in relevant models.

NATURE NEUROSCIENCE (2021)

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Article Multidisciplinary Sciences

Stroke subtype-dependent synapse elimination by reactive gliosis in mice

Xiaojing Shi et al.

Summary: This study showed that inhibiting phagocytosis of microglia and astrocytes in ischemic stroke improved neurobehavioral outcomes, attenuated brain damage, and prevented synapse loss. In hemorrhagic stroke, inhibiting phagocytosis of microglia/macrophages but not astrocytes improved neurobehavioral outcomes. Single-cell RNA sequencing revealed downregulation of phagocytosis-related processes in astrocytes of the hemorrhagic brain compared to the ischemic brain.

NATURE COMMUNICATIONS (2021)

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Article Neurosciences

Contribution of astrocytes to neuropathology of neurodegenerative diseases

Cigdem Acioglu et al.

Summary: Neuronal loss in neurodegenerative diseases is not solely caused by cell autonomous degeneration, but also involves non-cell autonomous mechanisms. Astrocytes, particularly reactive astrocytes, play key roles in these diseases with neurotoxic or neuroprotective phenotypes, and their responses to CNS pathology are complex and disease-specific.

BRAIN RESEARCH (2021)

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Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation

Tamara Zehnder et al.

Summary: Research has shown that mitochondrial biogenesis in astrocytes plays a critical role in ensuring correct synaptogenesis. The metabolic regulator PGC-1α and the metabotropic glutamate receptor mGluR5 play key roles in this process. Therefore, astrocytic mitochondria may be an important target for the treatment of neurodevelopmental and psychiatric disorders.

CELL REPORTS (2021)

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Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis

Tarik Seref Onur et al.

Summary: Research shows that glia cells play a crucial role in the formation and maintenance of synapses in neurodegenerative diseases. Lowering genes involved in synapse assembly can alleviate pathological and behavioral deficits. Conserved gene dysregulation is observed in patients with neurodegenerative diseases, fruit flies, and mice.

ELIFE (2021)

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Article Neurosciences

Cell adhesion molecules regulating astrocyte-neuron interactions

Christabel X. Tan et al.

Summary: Astrocytes play a key role in regulating synapse formation and function by interacting with neuronal synapses at tripartite synapses. Recent studies have shown a diverse range of cell adhesion-based mechanisms that mediate astrocyte-synapse interactions and influence both astrocyte morphological maturation and synapse development. These newly discovered molecular pathways in brain physiology have implications for both health and disease.

CURRENT OPINION IN NEUROBIOLOGY (2021)

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Article Neurosciences

Epigenetic control of region-specific transcriptional programs in mouse cerebellar and cortical astrocytes

Anna Welle et al.

Summary: This study reveals significant differences in gene expression and DNA methylation between astrocytes from the cerebral cortex and cerebellum, linked to region-specific transcription factor networks. The epigenetic variations suggest complex combinatorial regulation of regional astrocyte transcriptomes.

GLIA (2021)

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Article Neurosciences

Features of hippocampal astrocytic domains and their spatial relation to excitatory and inhibitory neurons

Ron Refaeli et al.

Summary: The study utilized CLARITY technology to conduct large-scale detection of 3D astrocytic domains, revealing different distributions of neuronal content in CA1 and BLA astrocytic domains. SST neurons were found to be located in close proximity to neighboring astrocytes, relative to PV and VIP neurons.

GLIA (2021)

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Review Biochemistry & Molecular Biology

Different Flavors of Astrocytes: Revising the Origins of Astrocyte Diversity and Epigenetic Signatures to Understand Heterogeneity after Injury

Alejandro Villarreal et al.

Summary: Astrocytes are a type of neuroglial cells that provide metabolic and structural support to neurons in the nervous system. In pathological conditions, astrocytes can undergo reactive astrogliosis, leading to phenotypic and transcriptional changes. The heterogeneity of astrocyte subpopulations in response to injury or other pathological conditions may be influenced by altered cellular signaling and cell type specification during development.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Neuroinflammatory astrocyte subtypes in the mouse brain

Philip Hasel et al.

Summary: This study investigated the transcriptome changes of mouse cortical astrocytes after an acute inflammatory stimulus, revealing rapid and drastic changes over time. By sequencing thousands of astrocytes at single-cell resolution, it was shown that inflammation causes a widespread response with distinct subtypes undergoing inflammatory transitions with defined transcriptomic profiles. Spatial transcriptomics and in situ hybridization were used to attribute specific inflammation-induced reactive astrocyte sub-states to certain brain regions.

NATURE NEUROSCIENCE (2021)

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Review Neurosciences

Astrocytic processes: from tripartite synapses to the active milieu

Alexey Semyanov et al.

Summary: A new concept of 'active milieu' is defined in this study, which integrates all components of nervous tissue into a dynamic information processing system, with a focus on the role of astrocytic processes. These processes are involved in reciprocal interactions with neuronal compartments and communicate with other elements of the nervous tissue within this framework.

TRENDS IN NEUROSCIENCES (2021)

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Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

Louis-Philippe Bernier et al.

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FRONTIERS IN CELLULAR NEUROSCIENCE (2021)

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Calcium Signals in Astrocyte Microdomains, a Decade of Great Advances

Annamaria Lia et al.

Summary: Astrocytes are recognized as crucial neuron-supporting elements in brain development and metabolism, and their communication with neurons through cytosolic Ca2+ elevations is a fundamental mechanism in modulating synaptic transmission. Recent studies using genetically encoded Ca2+ indicators and advanced microscopy techniques have elucidated key features of astrocyte Ca2+ activity in microdomains.

FRONTIERS IN CELLULAR NEUROSCIENCE (2021)

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Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes

Jiwen Li et al.

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NATURE COMMUNICATIONS (2021)

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Extensive transcriptional and chromatin changes underlie astrocyte maturation in vivo and in culture

Michael Lattke et al.

Summary: The study revealed extensive transcriptional and chromatin changes during astrocyte maturation in mice, and identified transcription factors that regulate the maturation of cultured astrocytes. Extrinsic signals can orchestrate the expression of multiple intrinsic regulators to induce transcriptional and chromatin changes underlying astrocyte maturation in a modular manner, improving cell maturity.

NATURE COMMUNICATIONS (2021)

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Molecular and functional properties of cortical astrocytes during peripherally induced neuroinflammation

Blanca Diaz-Castro et al.

Summary: The study explores the role of astrocytes in neuroinflammation triggered by peripheral bacterial endotoxin. Behavioral changes and astrocyte gene expression alterations peak with anhedonia and then return to normal levels. Despite significant astrocyte reactivity and behavioral changes, no evidence of altered neuronal survival or function in the PFC is found.

CELL REPORTS (2021)

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Activity-dependent modulation of synapse-regulating genes in astrocytes

Isabella Farhy-Tselnicker et al.

Summary: Research has shown that astrocytes regulate the formation and function of neuronal synapses during development through multiple signals, with some signals showing differential temporal and layer-enriched expression, regulated by neuronal activity. Alterations in astrocyte signaling lead to changes in the expression of synapse-regulating genes and synaptic development. Single-nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, as well as a cassette of genes that show layer-specific enrichment. It highlights the importance of coordinated signaling between astrocytes and neurons in the development of cortical circuits.

ELIFE (2021)

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Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

Nasna Nassir et al.

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Genetics and genomics of autism spectrum disorder: embracing complexity

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Astrocyte Development and Heterogeneity

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Deterministic Progenitor Behavior and Unitary Production of Neurons in the Neocortex

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Influence of Basement Membrane Proteins and Endothelial Cell-Derived Factors on the Morphology of Human Fetal-Derived Astrocytes in 2D

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Clonal Identity Determines Astrocyte Cortical Heterogeneity

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CEREBRAL CORTEX (2013)

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Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

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Emerging role for astroglial networks in information processing: from synapse to behavior

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TRENDS IN NEUROSCIENCES (2013)

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Acute and chronic glucocorticoid treatments regulate astrocyte-enriched nnRNAs in multiple brain regions in vivo

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Transgenic Mouse Models of Alzheimer Disease: Developing a Better Model as a Tool for Therapeutic Interventions

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CURRENT PHARMACEUTICAL DESIGN (2012)

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Coincident Generation of Pyramidal Neurons and Protoplasmic Astrocytes in Neocortical Columns

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Endothelial Cell-Derived Nitric Oxide Enhances Aerobic Glycolysis in Astrocytes via HIF-1α-Mediated Target Gene Activation

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Genomic Analysis of Reactive Astrogliosis

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JOURNAL OF NEUROSCIENCE (2012)

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Local generation of glia is a major astrocyte source in postnatal cortex

Woo-Ping Ge et al.

NATURE (2012)

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Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors

Nicola J. Allen et al.

NATURE (2012)

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Nitric oxide regulates astrocyte maturation in the hippocampus: Involvement of NOS2

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A role for glia in the progression of Rett's syndrome

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NATURE (2011)

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Astrocytes Prevent Abnormal Neuronal Development in the Fragile X Mouse

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JOURNAL OF NEUROSCIENCE (2010)

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Selective Changes in Thin Spine Density and Morphology in Monkey Prefrontal Cortex Correlate with Aging-Related Cognitive Impairment

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Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis

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Polycomb Limits the Neurogenic Competence of Neural Precursor Cells to Promote Astrogenic Fate Transition

Yusuke Hirabayashi et al.

NEURON (2009)

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Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code

Christian Hochstim et al.

CELL (2008)

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Endothelial cell-derived bone morphogenetic proteins regulate glial differentiation of cortical progenitors

Tetsuya Imura et al.

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The classical complement cascade mediates CNS synapse elimination

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Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells

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Astrocytes are active players in cerebral innate immunity

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Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development

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INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE (2004)

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Structural and quantitative analysis of astrocytes in the mouse hippocampus

K Ogata et al.

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Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains

EA Bushong et al.

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CNS synaptogenesis promoted by glia-derived cholesterol

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SCIENCE (2001)

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Abnormal development of dendritic spines in FMR1 knock-out mice

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Induction of astrocyte differentiation by endothelial cells

HY Mi et al.

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Dendritic spine structural anomalies in fragile-X mental retardation syndrome

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