Notch Signaling Imparts and Preserves Neural Stem Characteristics in the Adult Brain

Abstract

Although the role of Notch has been studied extensively in the developing nervous system, the embryonic lethality of Notch pathway mutants has hindered studies in the adult brain. The creation of cre/lox-mediated conditional gain- and loss-of-function mice has allowed us to investigate the role of Notch signaling in adult neural stem and progenitor cells. We have determined that Notch signaling is important for conferring stem cell characteristics upon neural precursor cells. Knocking-out Notch signaling in vivo results in neural progenitors, leaving the subependymal niche and migrating along the rostral migratory stream to the olfactory bulb, while overexpressing Notch results in retention of cells in the subependyma. Further, increased Notch signaling in progenitor cells resulted in the expression of stem cell markers in vivo as well as conferring the characteristics of self-renewal and multipotentiality upon subsequent isolation in vitro. Similar to what has been reported from the embryonic brain, the overexpression of Notch in neural precursor cells in vitro increased the numbers of neurospheres from the adult brain. Finally, overexpression of Notch1 in pure populations of progenitor cells (excluding neural stem cells) isolated by fluorescence activated cell sorting led to the formation of multipotent, self-renewing neurospheres from the non-neurosphere forming fraction. Hence, Notch overexpression confers stem cell properties upon progenitor cells and demonstrates that Notch signaling not only preserves stem cell characteristics, but that it can confer stem cell characteristics upon a subset of progenitor cells.