In the rodent CNS, neural stem cells persist in the adult subventricular zone (SVZ) of the lateral ventricle. In this work I examined the role of Hh-signaling in the progression of the stem cell lineage in the subventricular zone of the lateral ventricle, both at perinatal ages and in adulthood. After analyzing the effects of embryonic (E12.5) removal of Smo in the SVZ stem cell lineage, we concluded that Hh-signaling has multiple functions within the SVZ stem cell niche. Hh functions as a mitogen to promote the active proliferation of the transit-amplifying cells and, at the same time, acts as a critical factor for the maintenance of the self-renewing, slowly dividing stem cells. In addition Hh-signaling is required for the proper migration of neuroblasts, by regulating the expression of the chemorepellant Slit1.

To better understand whether Hh-signaling is simply needed for the establishment of the adult neurogenic niche or whether there is an ongoing requirement for the maintenance of this neural proliferative zone throughout adulthood, I subsequently examined the effects of postnatal (P60) removal of Smo in the SVZ stem cell lineage. This study demonstrated that the requirement for Hh-signaling in both stem cells and transit-amplifying cells extends throughout adulthood. Specifically I demonstrated that adult neural stem cells require Hh-signaling for their maintenance and that upon removal of this signaling pathway, these cells are progressively depleted. Notably, the mosaic loss of Hh-signaling impairs the adult stem cell niche permanently and cannot be compensated for by the remaining wt stem cells. Interestingly, the small population of normal stem cells in which Hh-signaling was spared did not replenish the niche over time, arguing that adult neural stem cells have a limited capacity for self-renewal.