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Astrocytes negatively regulate neurogenesis through the Jagged1-mediated notch pathway.

Journal article
Authors Ulrika Wilhelmsson
Maryam Faiz
Yolanda de Pablo
Marika Sjöqvist
Daniel Andersson
Åsa Widestrand
Maja Potokar
Matjaž Stenovec
Peter L P Smith
Noriko Shinjyo
Tulen Pekny
Robert Zorec
Anders Ståhlberg
Marcela Pekna
Cecilia Sahlgren
Milos Pekny
Published in Stem cells (Dayton, Ohio)
Volume 30
Issue 10
Pages 2320-9
ISSN 1549-4918
Publication year 2012
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Institute of Neuroscience and Physiology, Department of Pharmacology
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2320-9
Language en
Links dx.doi.org/10.1002/stem.1196
Keywords Astrocytes, Glial fibrillary acidic protein, Vimentin, Intermediate filaments, Neurogenesis
Subject categories Basic Medicine, Neurobiology

Abstract

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 cell-cell 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 γ-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.

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