title: Astrocytes negatively regulate neurogenesis through the Jagged1-mediated Notch pathway.
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.
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Wilhelmsson
authors.forename: Maryam
authors.initials: M
authors.lastname: Faiz
authors.forename: Yolanda
authors.initials: Y
authors.lastname: de Pablo
authors.forename: Marika
authors.initials: M
authors.lastname: Sjöqvist
authors.forename: Daniel
authors.initials: D
authors.lastname: Andersson
authors.forename: Asa
authors.initials: A
authors.lastname: Widestrand
authors.forename: Maja
authors.initials: M
authors.lastname: Potokar
authors.forename: Matjaž
authors.initials: M
authors.lastname: Stenovec
authors.forename: Peter L P
authors.initials: PL
authors.lastname: Smith
authors.forename: Noriko
authors.initials: N
authors.lastname: Shinjyo
authors.forename: Tulen
authors.initials: T
authors.lastname: Pekny
authors.forename: Robert
authors.initials: R
authors.lastname: Zorec
authors.forename: Anders
authors.initials: A
authors.lastname: Ståhlberg
authors.forename: Marcela
authors.initials: M
authors.lastname: Pekna
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
authors.forename: Milos
authors.initials: M
authors.lastname: Pekny
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation; D018920:Coculture Techniques; D004705:Endocytosis; D018507:Gene Expression Regulation, Developmental; D005904:Glial Fibrillary Acidic Protein; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D061251:Primary Cell Culture; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014746:Vimentin / Q000172:deficiency / Q000235:genetics*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D014746:Vimentin; D051153:Wnt Proteins; C528900:glial fibrillary astrocytic protein, mouse; D053829:Amyloid Precursor Protein Secretases