Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells.

By S. Hitoshi, Tania O. Alexson, V. Tropepe, D. Donoviel, A. Elia, J. Nye, R. A. Conlon, T. Mak, A. Bernstein, D. van der Kooy. Genes & Development, 2002

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Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-Jkappa, a key molecule in Notch signaling, by using RBP-Jkappa(-/-) embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains of RBP-Jkappa(-/-) or Notch1(-/-) mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1(+/-) adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.

Subfields: Developmental Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d9e9571d8319328e65b03cce2aa4a603db49a5cd

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Citations in the corpus

Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. (2011, neutral): “In the adult VZ-SVZ, loss of Notch signaling compromises stem cell self-renewal, while activation of this pathway enhances neurosphere formation (Hitoshi et al., 2002; Alexson et al., 2006).”
FAD-linked human Presenilin 1 variants impair environmental enrichment-induced hippocampal neural progenitor cell proliferation and differentiation in a non-cell-autonomous manner (2008, neutral): “Expression of FAD-Linked PS1 Variants Impairs EE-Induced Clonal Proliferation of Hippocampal Progenitor Cells in In Vitro Neurosphere Assays NPCs from hippocampus and other neurogenic regions of the adult mammalian brain can be isolated and grown in vitro as clonal sphere-forming cell colonies, term”
Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation (2004, background): “The basic helix-loop-helix genes Hes1 and Hes5 are essential effectors for Notch signalling, which regulates the maintenance of undifferentiated cells (Artavanis-Tsakonas et al., 1999; Gaiano and Fishell, 2002; Hitoshi et al., 2002; Honjo, 1996; Kageyama and Nakanishi, 1997; Selkoe and Kopan, 2003).”
Presenilin 1 mutants impair the self-renewal and differentiation of adult murine SVZ-neuronal progenitors via cell autonomous mechanisms involving Notch signaling (2010, background): “Likewise, PS1 / mice exhibit depleted numbers of adult NPCs, resulting from inhibition of their self-renewal capacity and altered cell cycle (Hitoshi et al., 2002).”
RBPJκ-Dependent Signaling Is Essential for Long-Term Maintenance of Neural Stem Cells in the Adult Hippocampus (2010, background): “…include Notchdependent pathways, which are essential for NSC maintenance, proliferation, and survival during development (Ohtsuka et al., 1999; Hitoshi et al., 2002; Androutsellis-Theotokis et al., 2006; Basak and Taylor, 2007; Mizutani et al., 2007) and control stem cell maintenance in…”
Notch signalling in solid tumours: a little bit of everything but not all the time (2011, background): “It is thought that Notch signalling in these neurospheres enhances their self-renewal capacity while inhibiting their differentiation into glial and neural progenitor cell”
Notch signalling in vertebrate neural development (2006, background): “, but seems to suppress both neuronal and astroglial differentiation in neurospheres derived from cultured neonatal forebrain cell”
Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. (2008, background): “Other investigators demonstrated that activation of Notch in mouse ESC derivatives after withdrawal of leukemia inhibitory factor (LIF) promoted exclusively neural differentiation, whereas inhibition of Notch blocked formation of neural progenitors.”
Brain tumour stem cells (2006, background): “Therefore, Notch has been suggested to function as a positive effector of self-renewal in adult neural stem cell”
The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex (2010, background): “Mouse mutants deficient in genes of the Notch signaling pathway support the view that this pathway plays a critical role in regulating the neural progenitor pool during neocortical development (ArtavanisTsakonas et al., 1999; Hitoshi et al., 2002; Yoon et al., 2004; Mizutani and Saito, 2005; Yoon an”
An essential switch in subunit composition of a chromatin remodeling complex during neural development. (2007, background): “Alternatively, our studies suggest that Notch signaling, which is essential for the self-renewal/proliferation of stem cells in the nervous system (Henrique et al., 1997; Hitoshi et al., 2002), is altered in Brg / multipotent neural progenitors (Figure 6).”
Radial glia cells are candidate stem cells of ependymoma. (2005, background): “SVZ.”
Essential Roles of Notch Signaling in Maintenance of Neural Stem Cells in Developing and Adult Brains (2010, background): “It has been shown that Notch signaling plays an important role in neurogenesis in both embryonic and adult brains (Chambers et al., 2001; Hitoshi et al., 2002; Mason et al., 2005; AndroutsellisTheotokis et al., 2006; Mizutani et al., 2007; Yoon et al., 2008).”