Dissecting Location-Specific Signaling Pathway Activity in the Neurogenic Niche

Abstract

The adult mammalian brain hosts two regions of quiescent neural stem cells that continually generate new neurons throughout life. One of these regions, the subventricular zone (SVZ), primarily produces immature neuroblasts that migrate and integrate into the olfactory bulb during neurogenesis. Stem cells in the SVZ are of interest because of their potential utility in brain repair. Strikingly, stem cell location within this germinal region determines the type of neuronal progeny that a given stem cell generates, and stem cells retain this positional identity upon culture or transplantation. However, the molecular mechanisms that regulate fate specification and proliferation in neural stem cells remain largely unknown, and it is not yet clear whether the intrinsic properties of particular stem cells affect their response to oncogenic events or damage. My lab has shown that active sonic hedgehog (Shh) signaling occurs in the ventral SVZ and is necessary and sufficient for the regulation of neuronal fate in a specific group of ventral stem cells. The dorsal region of the SVZ does not have high shh pathway activation; despite expression of most pathway components, these cells appear to be resistant to stimulation by Shh ligand. I hypothesize that Shh pathway signaling is actively repressed in the dorsal SVZ through expression of the Gli3 transcription factor, and that this repression is necessary to generate dorsal neural progeny. My thesis seeks to determine which downstream components of the shh pathway control proliferation and fate specification in dorsal stem cells.