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 2/2 Vim 2/2 ). We used primary astrocyte and neurosphere cocultures to demonstrate that astrocytes inhibit neuronal differentiation through a cell-cell contact. GFAP 2/2 Vim 2/2 astrocytes showed reduced endocytosis of Notch ligand Jagged1, reduced Notch signaling, and increased neuronal differentiation of neurosphere cultures. This effect of GFAP 2/2 Vim 2/2 astrocytes was abrogated in the presence of immobilized Jagged1 in a manner dependent on the activity of c-secretase. Finally, we used GFAP 2/2 Vim 2/2 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.

Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

“…We have previously shown that loss of the astrocytic intermediate filament cytoskeleton, composed of GFAP, vimentin, and nestin, affects Jagged-mediated Notch signaling during neurogenesis (13). As genes that are coexpressed in certain tissues have a higher probability to share a functional relationship (46), we screened tissue expression data in the GeneSapiens database (47) and found a strong positive correlation between the expression of vimentin and Jagged ligands in several tissues, e.g., in blood, breast, leukocytes, central nervous system, heart, kidney, muscle, and testis (Fig.…”

“…1D). We next expressed Dll4 and Jagged, and the chimeric ligands in mouse embryonic fibroblasts (MEFs) derived from WT (VimWT) and vimentin knockout (VimKO) mice and cocultured them with 293HEK reporter cells stably expressing full-length Notch 1 (FLN reporter cells) and then measured signal activation in FLN reporter cells stably expressing full-length Notch 1 using the CSL (CBF-1, suppressor of hairless, Lag-2)-based luciferase reporter system (FLN reporter cells) (13). Transfection efficiency and expression levels of the different proteins were confirmed by immunofluorescence and Western blot (WB).…”

“…Whereas IFs provide cells with mechanical stability, there is mounting evidence indicating that IFs are involved in a range of metabolic, signaling, and regulatory processes that are unrelated to mechanical functions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The vimentin IF has been shown to act as a scaffold for signaling proteins that regulate epithelial mesenchymal transition (EMT), cancer cell invasion, wound healing and tissue repair, tissue aging, as well as inflammatory signaling (3,4,(6)(7)(8)10).…”

Multiple roles of Ulk4 in neurogenesis and brain function

“…On the other hand, expression of Gfap and Vim, negative regulators of neurogenesis is markedly increased in Ulk4 mutants. 22 Together, Liu et al suggest that the Wnt pathway may play a critical role in mediating the effects of Ulk4 on NSCs.…”

The Role of Astrocytes in Tumor Growth and Progression

“…While astrocyte secreted factors have been shown to promote neurogenesis of normal adult NSCs, astrocytes within the microenvironment of brain tumors have also been shown to promote stem-like characteristics in BTSCs and enrich the stem cell population, thus worsening the malignancy of such brain tumors [125][126][127][128]. GBM CD133 + stem cells co-cultured both directly and indirectly with astrocytes show gene expression signatures known to be involved in GBM invasion and metastasis, such as a disintegrin and metalloproteinase domaincontaining protein 10 (ADAM10), hyaluronan synthase 2 (HAS2), and vascular cell adhesion molecule-1 (VCAM1).…”