Open AccessAstrocytes Negatively Regulate Neurogenesis Through the Jagged1‐Mediated Notch Pathway
Author(s) -
Wilhelmsson Ulrika,
Faiz Maryam,
de Pablo Yolanda,
Sjöqvist Marika,
Andersson Daniel,
Widestrand Åsa,
Potokar Maja,
Stenovec Matjaž,
Smith Peter L. P.,
Shinjyo Noriko,
Pekny Tulen,
Zorec Robert,
Ståhlberg Anders,
Pekna Marcela,
Sahlgren Cecilia,
Pekny Milos
Publication year - 2012
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1196
Subject(s) - neurogenesis , biology , notch signaling pathway , microbiology and biotechnology , glial fibrillary acidic protein , astrocyte , neurosphere , neural stem cell , gliogenesis , vimentin , progenitor cell , neuroscience , cellular differentiation , stem cell , signal transduction , central nervous system , adult stem cell , immunology , biochemistry , immunohistochemistry , gene
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. S TEM C ells 2012;30:2320–2329