Neural Stem Cell Positional Identity Corresponds to Differential mTORC1 Signaling and Tumor Susceptibility

Abstract

The origin and classification of neural stem cells (NSCs) has been a subject of intense investigation for the past two decades. Efforts to categorize NSCs based on their location, function, and expression have established that these cells are a heterogeneous pool in both the embryonic and adult brain. In this dissertation, heterogeneity is explored in the context of the ventricular-subventricular zone (V-SVZ), the largest stem cell niche in the mammalian brain. This niche generates up to an estimated 10,000 new neurons daily in the adult murine brain, and extends over a large spatial area with dorso-ventral and medio-lateral subdivisions. V-SVZ NSCs have a positional identity – their location within the niche determines the type and final location of the progeny they produce, thus rendering the V-SVZ a heterogeneous mix of NSC subtypes rather than a homogeneous group of equally plastic cells. Although we know that positional identity arises early in development, is defined by the expression of location-specific transcription factors, and predicts the type of progeny they produce, it is less clear if signaling responses within subpopulations of NSCs define their local proliferation or behavior. This dissertation seeks to answer this question by focusing on a neurodevelopmental disorder, Tuberous Sclerosis Complex (TSC), as a test case to determine if NSC positional identity affects cell signaling and/or tumor development. The data indicate that a specific subpopulation of ventral V-SVZ cells harbors increased basal growth pathway signaling through the mechanistic target of rapamycin complex 1 (mTORC1) and that removal of the upstream mTORC1 inhibitor, Tsc2, in this subpopulation is sufficient to produce nodules resembling patient tumors in a mouse model of TSC. This work reveals that positional identity also includes stereotypic basal signaling activity and that differing levels of growth pathway signaling in subregions of the V-SVZ are connected to distinct predispositions to disease phenotypes.