Molecular basis of astrocyte diversity and morphology across the CNS in health and disease

Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, and morphology across the mouse central nervous system (CNS). We identified shared and region-specific astrocytic genes and functions and explored the cellular origins...

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Published inScience (American Association for the Advancement of Science) Vol. 378; no. 6619; p. eadc9020
Main Authors Endo, Fumito, Kasai, Atsushi, Soto, Joselyn S, Yu, Xinzhu, Qu, Zhe, Hashimoto, Hitoshi, Gradinaru, Viviana, Kawaguchi, Riki, Khakh, Baljit S
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 04.11.2022
Subjects
Alzheimer Disease - genetics
Alzheimer Disease - pathology
Alzheimer's disease
Anatomy
Animals
Astrocytes
Astrocytes - classification
Astrocytes - metabolism
Astrocytes - ultrastructure
Biology
Biophysics
Biosynthesis
Bulk density
Central nervous system
Central Nervous System - cytology
Central Nervous System - metabolism
Cholesterol
Circuits
Cognitive ability
Cognitive tasks
Cognitive Tests
Complexity
CRISPR
Cytology
Disease Models, Animal
Disorders
Gene expression
Genes
Health risks
Humans
Lipid metabolism
Mice
Morphology
Nervous system
Neural networks
Neurodegenerative diseases
Neuroimaging
Neuronal-glial interactions
Neurotransmitters
Regional development
Risk
Similarity
Tissues
Transcriptome
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Summary:Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, and morphology across the mouse central nervous system (CNS). We identified shared and region-specific astrocytic genes and functions and explored the cellular origins of their regional diversity. We identified gene networks correlated with astrocyte morphology, several of which unexpectedly contained Alzheimer's disease (AD) risk genes. CRISPR/Cas9-mediated reduction of candidate genes reduced astrocyte morphological complexity and resulted in cognitive deficits. The same genes were down-regulated in human AD, in an AD mouse model that displayed reduced astrocyte morphology, and in other human brain disorders. We thus provide comprehensive molecular data on astrocyte diversity and mechanisms across the CNS and on the molecular basis of astrocyte morphology in health and disease.
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Author contributions: FE performed most experiments and analyzed data. AK and HH performed FAST. XY performed striatal scRNA-seq. JS conducted stereotactic AAV microinjections and made SaCas9 plasmids. ZQ and VG made PHP.eB:GfaABC1D Lck-GFP AAV. RK guided RNA-seq analyses. BSK conceived the study, planned and directed the experiments, and made figures with FE. BSK wrote the paper with help from FE; all authors approved final version.
Current address: Department of Molecular and Integrative Physiology, Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801-3704, USA
ISSN:0036-8075
1095-9203
DOI:10.1126/science.adc9020