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

Endo, Fumito and Kasai, Atsushi and Soto, Joselyn S. and Yu, Xinzhu and Qu, Zhe and Hashimoto, Hitoshi and Gradinaru, Viviana and Kawaguchi, Riki and Khakh, Baljit S. (2022) Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Science, 378 (6619). Art. No. adc9020. ISSN 0036-8075. doi:10.1126/science.adc9020.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription
Endo, Fumito0000-0003-4445-6707
Kasai, Atsushi0000-0002-1612-3078
Soto, Joselyn S.0000-0002-5869-9091
Yu, Xinzhu0000-0003-1244-0110
Hashimoto, Hitoshi0000-0001-6548-4016
Gradinaru, Viviana0000-0001-5868-348X
Kawaguchi, Riki0000-0002-2489-4825
Khakh, Baljit S.0000-0002-0939-1218
Additional Information:We thank F. Gao and the UCLA Neuroscience Genomics Core for assistance with RNA-seq, M. Gangwani for AAV delivery (Fig. 6F) and discussions, S. Cheong for help counting astrocytes (Fig. 1D), D. Geschwind for discussion about gene expression analysis, A. Huang and L. Wu for comments, and N. Okabe for IHC guidance. The sequencing core was supported partly by the Genetics, Genomics and Informatics Core of the Semel Institute of Neuroscience. Funding: B.S.K., J.S., F.E., and X.Y. were supported by the National Institutes of Health (NIH grants R01DA047444, R35NS111583, and R01AG0759655), an Allen Distinguished Investigator Award, a Paul G. Allen Frontiers Group advised grant of the Paul G. Allen Family Foundation, and the Ressler Family Foundation (B.S.K.). J.S.S. was supported by the National Science Foundation Graduate Research Fellowship Program (NSF-GRFP; DGE-2034835) and by a UCLA Eugene V. Cota-Robles Fellowship. A.K. and H.H. were supported by JSPS KAKENHI grants JP21K19335 (H.H.), JP20H00492 (H.H.), and JP20H03391 (A.K.); MEXT KAKENHI grant JP18H05416 (H.H.); AMED grant JP21dm0207117 (H.H.); and the Takeda Science Foundation, Japan (A.K., H.H.). V.G. was supported by the NIH (Pioneer Award DP1OD025535), the Vallee Foundation, the CZI Neurodegeneration Challenge Network, and the Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research (CLOVER) for technology development and dissemination.
Funding AgencyGrant Number
Paul G. Allen Family FoundationUNSPECIFIED
Ressler Family FoundationUNSPECIFIED
NSF Graduate Research FellowshipDGE-2034835
Japan Society for the Promotion of Science (JSPS)JP21K19335
Japan Society for the Promotion of Science (JSPS)JP20H00492
Japan Society for the Promotion of Science (JSPS)JP20H03391
Japan Society for the Promotion of Science (JSPS)JP18H05416
Osaka UniversityJP21dm0207117
Takeda Science FoundationUNSPECIFIED
Vallee FoundationUNSPECIFIED
CZI Neurodegeneration Challenge NetworkUNSPECIFIED
Beckman Institute for CLARITY, Optogenetics and Vector Engineering ResearchUNSPECIFIED
Issue or Number:6619
Record Number:CaltechAUTHORS:20221209-478595000.5
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:118282
Deposited By: Research Services Depository
Deposited On:12 Jan 2023 18:01
Last Modified:17 Jan 2023 18:15

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