Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain.
Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain.
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DOI：
10.3389/fnins.2021.621076
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发表时间：
2021
影响因子：
4.3
通讯作者：
Fernandes KJL
中科院分区：
文献类型：
--
作者：
Cochard LM;Levros LC Jr;Joppé SE;Pratesi F;Aumont A;Fernandes KJL
脑室-脑室下区（V-SVZ）是成年哺乳动物前脑中主要的神经原生态位。V-SVZ内的神经干/祖细胞（NSPC）活性受许多外在因素控制，其对NSPC增殖、存活和分化的下游作用通过有限数量的细胞内信号传导途径转导。在这里，我们研究了年龄相关的变化之间的关系，在NSPC输出和活性的信号转导途径下游的表皮生长因子受体（EGFR），一个主要的调节NSPC活动。生物化学实验表明，年龄相关的NSPC活性在体内的下降是伴随着V-SVZ生态位内的各种EGFR诱导的信号通路之间的选择性赤字。用培养的NSPCs进行的药理学功能丧失信号传导实验揭示了EGFR诱导的PI 3 K/AKT、MEK/ERK和mTOR信号传导模块调节的生物功能的重叠性和选择性。具体而言，虽然所有三个模块促进EGFR介导的NSPC增殖，但只有mTOR有助于NSPC存活，只有MEK/ERK抑制NSPC分化。使用功能获得体内遗传方法，我们将组成型活性EGFR构建体电穿孔到静止的EGFR阴性神经干细胞（qNSCs）亚群中; EGFR信号的异位激活使qNSCs能够在3个月大的早期成年小鼠中分裂，但在中年或携带家族性阿尔茨海默病突变的小鼠中则不能。因此，（i）单个EGFR诱导的信号传导途径对NSPC增殖、存活和分化具有可分离的作用，（ii）EGFR信号传导的活化足以刺激在成年早期进入qNSC细胞周期，和（iii）EGFR诱导的信号传导的增殖作用主要被与衰老和阿尔茨海默病相关的抗增殖信号所覆盖。
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.
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