Journal
STEM CELLS
Volume 30, Issue 10, Pages 2320-2329Publisher
WILEY
DOI: 10.1002/stem.1196
Keywords
Astrocytes; Glial fibrillary acidic protein; Vimentin; Intermediate filaments; Neurogenesis
Categories
Funding
- Swedish Medical Research Council [11548]
- AFA Research Foundation
- ALF Goteborg [11392]
- Sten A. Olsson Foundation for Research and Culture
- Soderberg Foundations
- Hjarnfonden
- Swedish Stroke Foundation
- Swedish Society for Medical Research
- Free Mason Foundation
- Amlov's Foundation
- E. Jacobson's Donation Fund
- NanoNet COST Action [BM1002]
- EU FP 7 Program EduGlia [237956]
- EU FP 7 Program Target-BraIn [279017]
- Trygg-Hansa
- Academy of Finland
- Turku Graduate School for Biomedical Sciences
- Research Agency of Slovenia [P30310, J30031, J30133, J34051, J34146, J33632]
- Austrian Science Fund (FWF) [P30310] Funding Source: Austrian Science Fund (FWF)
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Adult neurogenesis is regulated by a number of cellular players within the neurogenic niche. Astrocytes participate actively in brain development, regulation of the mature central nervous system (CNS), and brain plasticity. They are important regulators of the local environment in adult neurogenic niches through the secretion of diffusible morphogenic factors, such as Wnts. Astrocytes control the neurogenic niche also through membrane-associated factors, however, the identity of these factors and the mechanisms involved are largely unknown. In this study, we sought to determine the mechanisms underlying our earlier finding of increased neuronal differentiation of neural progenitor cells when cocultured with astrocytes lacking glial fibrillary acidic protein (GFAP) and vimentin (GFAP-/-Vim-/-). We used primary astrocyte and neurosphere cocultures to demonstrate that astrocytes inhibit neuronal differentiation through a cellcell contact. GFAP-/-Vim-/- astrocytes showed reduced endocytosis of Notch ligand Jagged1, reduced Notch signaling, and increased neuronal differentiation of neurosphere cultures. This effect of GFAP-/-Vim-/- astrocytes was abrogated in the presence of immobilized Jagged1 in a manner dependent on the activity of ?-secretase. Finally, we used GFAP-/-Vim-/- mice to show that in the absence of GFAP and vimentin, hippocampal neurogenesis under basal conditions as well as after injury is increased. We conclude that astrocytes negatively regulate neurogenesis through the Notch pathway, and endocytosis of Notch ligand Jagged1 in astrocytes and Notch signaling from astrocytes to neural stem/progenitor cells depends on the intermediate filament proteins GFAP and vimentin. STEM Cells2012;30:23202329
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