Abstract
Neural stem/progenitor cells (NSPCs) of the ventricular-subventricular zone (V-SVZ) are candidate cells of origin for many brain tumors. However, whether NSPCs in different locations within the V-SVZ differ in susceptibility to tumorigenic mutations is unknown. Here, single-cell measurements of signal transduction intermediates in the mechanistic target of rapamycin complex 1 (mTORC1) pathway reveal that ventral NSPCs have higher levels of signaling than dorsal NSPCs. These features are linked with differences in mTORC1-driven disease severity: introduction of a pathognomonic Tsc2 mutation only results in formation of tumor-like masses from the ventral V-SVZ. We propose a direct link between location-dependent intrinsic growth properties imbued by mTORC1 and predisposition to tumor development.
Highlights
The ventricular–subventricular zone (V-SVZ) is the largest stem cell niche in the mammalian brain and is active during early postnatal development in both human and mouse (Guerrero-Cazares et al, 2011; Sanai et al, 2011)
Empty spiracles homeobox 1 (EMX1), which is expressed in developing cortex and in stem cells of the dorsal V-SVZ, was abundant in tubers (Fig 1A)
EMX1 was largely absent in subependymal giant cell astrocytomas (SEGAs), suggesting that these two differentially localized malformations in tuberous sclerosis complex (TSC) patients originate from distinct progenitor populations and that periventricular tumors are enriched for ventral markers
Summary
The ventricular–subventricular zone (V-SVZ) is the largest stem cell niche in the mammalian brain and is active during early postnatal development in both human and mouse (Guerrero-Cazares et al, 2011; Sanai et al, 2011). To analyze per-cell mTORC1 activity in V-SVZ subpopulations, dorsal and ventral NSPCs were dissected from neonatal mice and cultured as monolayers (Fig S1A).
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