Abstract
The ventricular-subventricular zone (V-SVZ) is the principal neurogenic niche in the adult mammalian forebrain. Neural stem/progenitor cell (NSPC) activity within the V-SVZ is controlled by numerous of extrinsic factors, whose downstream effects on NSPC proliferation, survival and differentiation are transduced via a limited number of intracellular signaling pathways. Here, we investigated the relationship between age-related changes in NSPC output and activity of signaling pathways downstream of the epidermal growth factor receptor (EGFR), a major regulator of NSPC activity. Biochemical experiments indicated that age-related decline of NSPC activity in vivo is accompanied by selective deficits amongst various EGFR-induced signal pathways within the V-SVZ niche. Pharmacological loss-of-function signaling experiments with cultured NSPCs revealed both overlap and selectivity in the biological functions modulated by the EGFR-induced PI3K/AKT, MEK/ERK and mTOR signaling modules. Specifically, while all three modules promoted EGFR-mediated NSPC proliferation, only mTOR contributed to NSPC survival and only MEK/ERK repressed NSPC differentiation. Using a gain-of-function in vivo genetic approach, we electroporated a constitutively active EGFR construct into a subpopulation of quiescent, EGFR-negative neural stem cells (qNSCs); this ectopic activation of EGFR signaling enabled qNSCs to divide in 3-month-old early adult mice, but not in mice at middle-age or carrying familial Alzheimer disease mutations. Thus, (i) individual EGFR-induced signaling pathways have dissociable effects on NSPC proliferation, survival, and differentiation, (ii) activation of EGFR signaling is sufficient to stimulate qNSC cell cycle entry during early adulthood, and (iii) the proliferative effects of EGFR-induced signaling are dominantly overridden by anti-proliferative signals associated with aging and Alzheimer’s disease.
Highlights
The ventricular-subventricular zone (V-SVZ) of the forebrain lateral ventricles is a highly organized and tightly regulated environment that is permissive for adult neurogenesis (Lim and Alvarez-Buylla, 2016)
To more precisely describe the proliferative and neurogenic changes occurring during this period, we used immunohistochemistry to quantify the numbers of Ki67 + proliferating cells, Mammalian achaete-scute homolog-1 (Mash1) + transit amplifying progenitor (TAP) and Doublecortin (DCX) + neuroblasts in the V-SVZ at multiple ages between juvenile (1-month-old) and middle-aged (11month-old) timepoints
In line with this, when we processed electroporated V-SVZs for neurosphere cultures, we found that epidermal growth factor receptor (EGFR)-CA-induced activation of quiescent neural stem cell (qNSC) did not lead to generation of labeled neurospheres (Figures 4Q,R); this is consistent with the electroporated qNSCs being separate from the self-renewing, neurosphere-forming activated neural stem cell (aNSC) lineage (Joppe et al, 2020)
Summary
The ventricular-subventricular zone (V-SVZ) of the forebrain lateral ventricles is a highly organized and tightly regulated environment that is permissive for adult neurogenesis (Lim and Alvarez-Buylla, 2016). Integration of the microenvironmental signals that regulate activity of NSCs and TAPs (referred to collectively as neural stem/progenitor cells, NSPCs) is mediated by a limited number of intracellular signaling pathways (Lennington et al, 2003; Faigle and Song, 2013). It is modulation of these intracellular signaling pathways that controls NSPC survival, proliferation and differentiation (Lim and AlvarezBuylla, 2016; Cutler and Kokovay, 2020). Previous studies have shown that mTOR, a downstream target of the PI3K/Akt pathway, is essential during EGFR-mediated NSPC proliferation; mTOR inhibition blocked
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