Genetic targeting of neurogenic precursors in the adult forebrain ventricular epithelium

Joppé, Sandra E.; Cochard, Loïc M.; Levros, Louis‐Charles; Hamilton, Laura; Ameslon, Pierre; Aumont, Anne; Barnabé-Heider, Fanie; Fernandes, Karl J.L.

doi:10.26508/lsa.202000743

Cited by 5 publications

(10 citation statements)

References 56 publications

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“…Interestingly, and despite only transient expression of the EGFR-CA plasmid, analysis of a cohort of electroporated mice at 4 weeks post-electroporation revealed trends for EGFR-CA to eventually decrease YFP + cells within the V-SVZ and increase YFP + cells in the OB (Figures 4L-P). In line with this, when we processed electroporated V-SVZs for neurosphere cultures, we found that EGFR-CA-induced activation of qNSCs 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 aNSC lineage (Joppe et al, 2020).…”

Section: Egfr-ca Can Promote Neurogenic Activity Of Qnscs In Vivosupporting

confidence: 80%

“…Recently, we showed that adult brain electroporation can be used to genetically target a subpopulation of ventricle-contacting, GFAP-expressing cells within the qNSC population ( Joppe et al, 2020 ). In that study, lineage-tracing showed these electroporated precursors produced small numbers of olfactory bulb neurons in vivo and did so independently of the neurosphere-forming aNSC lineage.…”

Section: Resultsmentioning

confidence: 99%

“…Since NSPC proliferation required activity of all three branches of EGFR signaling that we examined, we tested whether upregulation of EGFR signaling would be sufficient to trigger proliferation of qNSCs in vivo . We recently found that a population of quiescent, ventricle-contacting neural precursors that produces small numbers of olfactory bulb neurons can be genetically targeted by adult brain electroporation ( Joppe et al, 2020 ). We therefore used this approach to transfect these quiescent precursors in 3-month-old adult male mice with a constitutively active EGFR construct (EGFR-CA).…”

Section: Discussionmentioning

confidence: 99%

“…For the electroporation in an Alzheimer model, we used 6-month old female 3xTg mice and their WT control strain ( n = 5 per group). Adult brain electroporation was conducted as described previously ( Barnabe-Heider et al, 2008 ; Joppe et al, 2015 ; Joppe et al, 2020 ). Plasmids ( Supplementary Table 1 ) were amplified by using an endotoxin-free 40 min Fast Plasmid Maxiprep Kit (Biotool), then purified and concentrated by ethanol precipitation.…”

Section: Methodsmentioning

confidence: 99%

“…First, we used in vitro pharmacological approaches to better understand how the EGFR-triggered AKT, ERK and mTOR signaling cascades coordinate the processes of NSPC survival, proliferation and/or differentiation. We then used an in vivo electroporation approach to ectopically express and activate EGFR signaling in a subpopulation of ventricle-contacting qNSCs ( Joppe et al, 2020 ) in models of the early adult, middle-aged, and Alzheimer V-SVZ niche. Altogether, this work provides us with a clearer understanding of the potential for manipulating EGFR-induced signaling pathways for enhancing V-SVZ neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain

et al. 2021

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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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Section: Egfr-ca Can Promote Neurogenic Activity Of Qnscs In Vivosupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain

et al. 2021

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Application of Lineage Tracing in Central Nervous System Development and Regeneration

Zhuang

Zhang

et al. 2023

Mol Biotechnol

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The central nervous system (CNS) is a complicated neural network. The origin and evolution of functional neurons and glia cells remain unclear, as do the cellular alterations that occur during the course of cerebral disease rehabilitation. Lineage tracing is a valuable method for tracing specific cells and achieving a better understanding of the CNS. Recently, various technological breakthroughs have been made in lineage tracing, such as the application of various combinations of fluorescent reporters and advances in barcode technology. The development of lineage tracing has given us a deeper understanding of the normal physiology of the CNS, especially the pathological processes. In this review, we summarize these advances of lineage tracing and their applications in CNS. We focus on the use of lineage tracing techniques to elucidate the process CNS development and especially the mechanism of injury repair. Deep understanding of the central nervous system will help us to use existing technologies to diagnose and treat diseases.

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A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis

Baur

Abdullah

Mandl

et al. 2020

Preprint

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Neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ) contribute to olfaction by being the origin of most adult-born olfactory bulb (OB) interneurons. The current consensus maintains that adult NSCs are radial glialike progenitors apically contacting the lateral ventricle and generating intermediate progenitors migrating at the basal V-SVZ. Whether basal NSCs are present in the V-SVZ is unknown. We here used genetic tagging of NSCs in vivo and additional labelling approaches to reveal that basal NSCs lacking apical attachment represent the largest NSC type in the postnatal V-SVZ from birth onwards. Despite dividing faster than their apical counterpart, basal NSCs still undergo long-term self-renewal and quiescence. Unlike apical NSCs, they are largely devoid of primary cilia and Prominin-1, Nestin and glial fibrillary acidic protein (GFAP) immunoreactivity. Six weeks after viral tagging of apical cells, few descendant cells were detected in the basal V-SVZ, including Sox9+ progenitors and GFAP+ astrocytes, and very rare new neurons in the OB, indicating that adult-born OB neurons originate from basal and not apical NSCs. Consistent with this, we found that pregnancy, a physiological modulator of adult OB neurogenesis, selectively increases the number of basal but not apical NSCs. Lastly, we find that apical NSCs display the highest levels of Notch activation in the neural lineage, and that selective apical downregulation of Notch-signaling effector Hes1 decreases Notch activation while increasing proliferation across the V-SVZ. Thus, apical NSCs act essentially as neurogenesis gatekeepers by modulating Notch-mediated lateral inhibition of proliferation in the adult V-SVZ.Graphical AbstractHighlightsBasal NSCs are the most abundant stem cell type in the adult V-SVZ from birth onwards.Apical and basal NSCs display distinct characteristics and cell cycle progression dynamics.Apical NSCs are not the main source of newly generated adult OB interneurons.Apical NSCs regulate intermediate progenitor proliferation by orchestrating Notch-mediated lateral inhibition.

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Genetic targeting of neurogenic precursors in the adult forebrain ventricular epithelium

Cited by 5 publications

References 56 publications

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

Application of Lineage Tracing in Central Nervous System Development and Regeneration

A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis

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