Astrocytes Negatively Regulate Neurogenesis Through the Jagged1-Mediated Notch Pathway§

Authors

  • Ulrika Wilhelmsson,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Maryam Faiz,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Yolanda de Pablo,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Marika Sjöqvist,

    1. Turku Centre for Biotechnology, University of Turku, Turku, Finland
    2. Department of Biosciences, Åbo Akademi University, Turku, Finland
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  • Daniel Andersson,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Åsa Widestrand,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Maja Potokar,

    1. Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
    2. Celica Biomedical Center, Ljubljana, Slovenia
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  • Matjaž Stenovec,

    1. Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
    2. Celica Biomedical Center, Ljubljana, Slovenia
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  • Peter L. P. Smith,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Noriko Shinjyo,

    1. Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Tulen Pekny,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Robert Zorec,

    1. Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
    2. Celica Biomedical Center, Ljubljana, Slovenia
    3. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
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  • Anders Ståhlberg,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Marcela Pekna,

    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Cecilia Sahlgren,

    1. Turku Centre for Biotechnology, University of Turku, Turku, Finland
    2. Department of Biosciences, Åbo Akademi University, Turku, Finland
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  • Milos Pekny

    Corresponding author
    1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    • Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 440, SE-405 30 Gothenburg, Sweden

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    • Telephone: +46 31 786 3269; Fax: +46 31 416 108


  • Author contributions: U.W. and M.F.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; Y.d.P and D.A.: conception and design, collection and/or assembly of data, and data analysis and interpretation, M. Sjöqvist, Å.W., M. Potokar, M. Stenovec, P.L.P.S., and T.P.: collection and/or assembly of data and data analysis and interpretation; N.S.: provision of study material or patients; R.Z. and C.S.: conception and design, financial support, and data analysis and interpretation; A.S.: conception and design; M. Pekna: conception and design, data analysis and interpretation, and manuscript writing; M. Pekny: conception and design, financial support, data analysis and interpretation, and manuscript writing. U.W. and M.F. contributed equally to this article. Y.d.P. and M. Sjöqvist, contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS July 15, 2012.

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. STEM Cells2012;30:2320–2329

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