Hedgehog Signaling in the Subventricular Zone Is Required for Both the Maintenance of Stem Cells and the Migration of Newborn Neurons

Abstract

We examined the postnatal consequences of removing Hedgehog signaling within the adult stem cell niche. Although at birth the subventricular zone appears normal in mice lacking Hedgehog signaling, by postnatal day 8 it is greatly impaired, and cell death is increased. In addition, both the quiescent B stem cell population and transit-amplifying C cells become depleted postnatally. In contrast, the A cell population expands precociously, mostly fails to migrate to the olfactory bulbs, and is ultimately also depleted by postnatal day 30. In vitro and in vivo analyses demonstrate that this failure in migration is a result of nonautonomous signaling, possibly caused by a reduction in Slit1 ligand in A cells. These results suggest that Hedgehog signaling is required for the maintenance of the B and C cell populations and indirectly for the migration of the neurons that are generated from the adult stem cell niche.

Mosaic Removal of Hedgehog Signaling in the Adult SVZ Reveals That the Residual Wild-Type Stem Cells Have a Limited Capacity for Self-Renewal

“…5f-h). Indeed, this mutant phenotype closely resembles that observed in our previous analyses (Machold et al, 2003;Balordi and Fishell, 2007), where Smo gene function in the niche was removed by E12.5. In addition Nestin CreER/ϩ ;Smo c/c progenitors from the SVZ gave rise to fewer neurospheres (70% reduction) than controls (Fig.…”

“…It is also required for neural precursor proliferation (Dahmane and Ruiz i Altaba, 1999;Rowitch et al, 1999;Wallace, 1999;Wechsler-Reya and Scott, 1999;Britto et al, 2002), the maintenance of adult neural stem cells (Lai et al, 2003;Machold et al, 2003;Palma et al, 2005;Balordi and Fishell, 2007) and the migration of newborn neurons (Balordi and Fishell, 2007).…”

“…These studies have demonstrated that the periventricular slow dividing GFAPϩ cells (B cells) function as stem cells, which generate a transit-amplifying population (C cells) that in turn gives rise to young migrating neuroblasts (A cells). Previous studies (Machold et al, 2003;Balordi and Fishell, 2007) showed that when Smoothened (Smo), an obligate cellautonomous effector of Hh signaling , is conditionally removed from neural progenitors by embryonic day 12.5 (E12.5) (using a Nestin Cre driver line), there is no obvious effect on the SVZ at birth, suggesting that from E12.5 until birth Hh signaling is not required to maintain telencephalic progenitor proliferation. In contrast, during the first two postnatal weeks, neural progenitors within the SVZ become rapidly depleted.…”

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…Midgestation removal of Shh, Smo or Kif3a -a crucial component of the primary cilium -results in a severe depletion of progenitors in the neurogenic regions (Balordi and Fishell, 2007a;Han et al, 2008;Machold et al, 2003). In these mutant mice, the stem cell compartments suffer from extensive early postnatal cell apoptosis, resulting in severely perturbed olfactory bulb (OB) interneuron and DG neuronal production, indicating that early SHH signaling is required for the survival of NSCs.…”

“…Expression of the glioma-associated oncogene proteins (GLIs) ends as the lineage progresses from NSCs to TACs. In addition, whereas GLI2 and GLI3 are expressed in mature astrocytes and NSCs throughout the SVZ and the rest of the brain, GLI1 is present in only a subset of NSCs and astrocytes (hatched orange line), possibly in regions where HH signaling is the highest (Balordi and Fishell, 2007a;Garcia et al, 2010;Petrova et al, 2013). function to maintain the undifferentiated and proliferation-capable state of NSCs in the adult forebrain. Consistent with this, it was recently found that overactivation of the SHH pathway in SZV NSCs (by deletion of Ptch1) promotes NSC self-renewal at the expense of TAC and neuron production, through inducing NOTCH signaling and symmetric cell divisions (Ferent et al, 2014).…”