Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal.

Abstract

The Smoothened gene is necessary for cells to transduce hedgehog signaling. Although we and others have previously shown that embryonic removal of Smoothened in the neural tube results in a loss of stem cells from the postnatal subventricular zone, it was unclear whether this reflected a requirement for hedgehog signaling in the establishment or maintenance of the adult niche. Here, we have examined the consequences of conditional removal of Smoothened gene function within the subventricular zone of the adult neural stem cell niche. We observe that both proliferation and neurogenesis are compromised when hedgehog signaling is removed from subventricular zone stem cells. Moreover, even after a 10 month survival period, the stem cell niche fails to recover. It has been reported that the adult subventricular zone quickly rebounds from an antimitotic insult by increasing proliferation and replenishing the niche. During this recovery, it has been reported that hedgehog signaling appears to be upregulated. When mice in which hedgehog signaling in the subventricular zone has been strongly attenuated are given a similar antimitotic treatment, recovery is limited to the reduced level of proliferation and neurogenesis observed before the mitotic insult. Furthermore, the limited recovery that is observed appears to be largely restricted to the minority of neural stem cells that escape the conditional inactivation of Smoothened gene function. These results demonstrate that ongoing hedgehog signaling is required to maintain adult neural stem cells and that their ability to self-renew is limited.