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

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<jats:p>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 <jats:italic>RBP-J</jats:italic>κ, a key molecule in Notch signaling, by using <jats:italic>RBP-J</jats:italic>κ<jats:sup>−/−</jats:sup> 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<jats:italic>RBP-J</jats:italic>κ<jats:sup>−/−</jats:sup> or <jats:italic>Notch1</jats:italic><jats:sup>−/−</jats:sup> mice. Neural stem cells also are depleted in embryonic brains deficient for the <jats:italic>presenilin1</jats:italic> (<jats:italic>PS1</jats:italic>) gene, a key regulator in Notch signaling, and are reduced in <jats:italic>PS1</jats:italic><jats:sup>+/−</jats:sup> 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.</jats:p>

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  • Genes & Development

    Genes & Development 16 (7), 846-858, 2002-04-01

    Cold Spring Harbor Laboratory

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