title: Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles for Asef during Development and after Injury.
abstract: Lineage development is a stepwise process, governed by stage-specific regulatory factors and associated markers. Astrocytes are one of the principle cell types in the CNS and the stages associated with their development remain very poorly defined. To identify these stages, we performed gene-expression profiling on astrocyte precursor populations in the spinal cord, identifying distinct patterns of gene induction during their development that are strongly correlated with human astrocytes. Validation studies identified a new cohort of astrocyte-associated genes during development and demonstrated their expression in reactive astrocytes in human white matter injury (WMI). Functional studies on one of these genes revealed that mice lacking Asef exhibited impaired astrocyte differentiation during development and repair after WMI, coupled with compromised blood-brain barrier integrity in the adult CNS. These studies have identified distinct stages of astrocyte lineage development associated with human WMI and, together with our functional analysis of Asef, highlight the parallels between astrocyte development and their reactive counterparts associated with injury.
  
  
  
  Astrocytes play a central role in CNS function and associated diseases. Yet the mechanisms that control their development remain poorly defined. Using the developing mouse spinal cord as a model system, we identify molecular changes that occur in developing astrocytes. These molecular signatures are strongly correlated with human astrocyte expression profiles and validation in mouse spinal cord identifies a host of new genes associated with the astrocyte lineage. These genes are present in reactive astrocytes in human white matter injury, and functional studies reveal that one of these genes, Asef, contributes to reactive astrocyte responses after injury. These studies identify distinct stages of astrocyte lineage development and highlight the parallels between astrocyte development and their reactive counterparts associated with injury.
authors.affiliation: Program in Developmental Biology.|Center for Cell and Gene Therapy.
authors.forename: Lesley S
authors.initials: LS
authors.lastname: Chaboub
authors.affiliation: Center for Cell and Gene Therapy.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Manalo
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77230.
authors.forename: Hyun Kyoung
authors.identifier: 0000-0001-5793-4398
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Center for Cell and Gene Therapy.
authors.forename: Stacey M
authors.identifier: 0000-0003-2716-4948
authors.initials: SM
authors.lastname: Glasgow
authors.affiliation: Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Fengju
authors.identifier: 0000-0001-8744-9895
authors.initials: F
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Department of Cell Biology, Duke University, Durham, North Carolina 27710, and.
authors.forename: Chay T
authors.initials: CT
authors.lastname: Kuo
authors.affiliation: Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas 77030.|Department of Medicine and.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Carrie A
authors.identifier: 0000-0002-0261-0406
authors.initials: CA
authors.lastname: Mohila
authors.affiliation: Program in Developmental Biology, deneen@bcm.edu.|Center for Cell and Gene Therapy.|Department of Neuroscience, and.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77230.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Deneen
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064067:Rho Guanine Nucleotide Exchange Factors; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology*; D058630:Spinal Cord Regeneration / Q000502:physiology*; D013997:Time Factors
chemical_list: C547838:Arhgef4 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors
keywords: astrocyte precursors; blood–brain barrier; reactive astrocytes; white matter injury