In Vivo Clonal Analysis Reveals Self-Renewing and Multipotent Adult Neural Stem Cell Characteristics

Bonaguidi, Michael A.; Wheeler, Michael A.; Shapiro, Jason S.; Stadel, Ryan P.; Sun, George; Ming, Guo Li; Song, Hongjun

doi:10.1016/j.cell.2011.05.024

Cited by 767 publications

(990 citation statements)

References 54 publications

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“…We did not observe increases in Hes5CreER T2 -derived polymorphic astrocytes (S100β + ) over time, confirming results from clonal analysis of SGZ NSCs 11 . We also did not observe Hes5 + NSC-derived oligodendrocytes; hence, in accordance with other reports, adult DG NSCs are mainly neurogenic and do not contribute majorly to gliogenesis in vivo 6,11,14,17,47,49 .…”

Section: Hes5creersupporting

confidence: 92%

Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors

et al. 2012

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neural stem/progenitor cells generate neurons in the adult hippocampus. neural stem cells produce transient intermediate progenitors (type-2 cells), which generate neuroblasts (type-3 cells) that exit the cell cycle, and differentiate into neurons. The precise dynamics of neuron production from the neural stem cells remains controversial. Here we lineage trace notchdependent neural stem cells in the dentate gyrus and show that over 7-21 days, the progeny of the neural stem cells progress through an Ascl1 high intermediate stage (type-2a) to neuroblasts. However, contrary to predictions, this Ascl1 high population is not an amplifying intermediate, but it differentiates into mitotic Tbr2 + early neuroblasts, which in turn expand the lineage. After 100 days, the majority of the neural stem cell progeny are neuroblasts or postmitotic neurons. Hence, the neural stem cells require many weeks to generate differentiated neurons. on the basis of this temporal delay in differentiation and population expansion, we propose that the neural stem cell and early neuroblast divisions drive dentate gyrus neurogenesis and not the amplification of type-2a intermediate progenitors as was previously thought.

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Section: Hes5creersupporting

confidence: 92%

Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors

et al. 2012

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“…Embryonic cortical stem cells have smooth spheroid cell bodies that extend long smooth processes, which enable newly formed neurons to migrate into the cortical plate (30). In the adult dentate gyrus, however, the observation of individual clones suggest that adult-born neurons do not migrate alongside the radial process of their mother cells, but instead migrate tangentially away from it, before integrating into the GCL (24,31). We therefore believe that the reasons for their complex radial morphologies lie in the regulatory mechanisms of the neurogenic niche.…”

mentioning

confidence: 99%

“…RGL neural stem cells of the adult dentate gyrus also express astrocytic markers, but comprise a heterogeneous population based on the molecular markers they express, the morphologies they exhibit (17)(18)(19)(20)(21)(22), and their fate (23)(24)(25)(26)(27)(28). Nestin-GFP-positive RGL stem cells account for more than 70% of RGL stem cells in the SGZ of the dentate gyrus (24), but it was recently found that not all Nestin-GFP-positive cells with RGL morphology have stem cell properties (29): type β cells, which arborize in the granule cell layer (GCL) but do not reach the molecular layer (ML) of the dentate gyrus, account for 26% of Nestin-GFP-positive RGL stem cells. They express stem cell (Sox1, Sox2, Prominin 1, GFAP, and Nestin) and astrocytic [GFAP, glial glutamate tranporter 1 (GLT1), and S100β] markers but do not proliferate.…”

mentioning

confidence: 99%

Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

Moss

Gebara

Bushong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

110

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Adult hippocampal neurogenesis relies on the activation of neural stem cells in the dentate gyrus, their division, and differentiation of their progeny into mature granule neurons. The complex morphology of radial glia-like (RGL) stem cells suggests that these cells establish numerous contacts with the cellular components of the neurogenic niche that may play a crucial role in the regulation of RGL stem cell activity. However, the morphology of RGL stem cells remains poorly described. Here, we used light microscopy and electron microscopy to examine Nestin-GFP transgenic mice and provide a detailed ultrastructural reconstruction analysis of Nestin-GFP-positive RGL cells of the dentate gyrus. We show that their primary processes follow a tortuous path from the subgranular zone through the granule cell layer and ensheathe local synapses and vasculature in the inner molecular layer. They share the ensheathing of synapses and vasculature with astrocytic processes and adhere to the adjacent processes of astrocytes. This extensive interaction of processes with their local environment could allow them to be uniquely receptive to signals from local neurons, glia, and vasculature, which may regulate their fate.adult neurogenesis | adult neural stem cell | neurogenic niche | electron microscopy | hippocampus N eurogenesis in the adult mouse brain primarily occurs within discrete niches, the subventricular zone (SVZ), and the subgranular zone (SGZ) of the dentate gyrus, supplying new neurons to the olfactory bulb and the dentate gyrus, respectively (1-3). Neural stem cells of these niches can be activated to divide and generate other stem cells, astrocytes, or new neurons (4, 5). Newborn neurons of the dentate gyrus have the capacity to integrate into the existing hippocampal circuitry (6-8), influencing processes such as learning and memory (9-11) as well as stress and depression (12).Radial glia-like (RGL) neural stem cells of the SVZ, which supply the olfactory bulb with newborn neurons and astrocytes, express astrocytic markers and form elegant pinwheel structures (13-16). RGL neural stem cells of the adult dentate gyrus also express astrocytic markers, but comprise a heterogeneous population based on the molecular markers they express, the morphologies they exhibit (17-22), and their fate (23-28). Nestin-GFP-positive RGL stem cells account for more than 70% of RGL stem cells in the SGZ of the dentate gyrus (24), but it was recently found that not all Nestin-GFP-positive cells with RGL morphology have stem cell properties (29): type β cells, which arborize in the granule cell layer (GCL) but do not reach the molecular layer (ML) of the dentate gyrus, account for 26% of Nestin-GFP-positive RGL stem cells. They express stem cell (Sox1, Sox2, Prominin 1, GFAP, and Nestin) and astrocytic [GFAP, glial glutamate tranporter 1 (GLT1), and S100β] markers but do not proliferate. In contrast, type α cells, which extend across the GCL and arborize in the inner ML, account for 74% of Nestin-GFP-positive RGL cells. They express stem...

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“…Under basal conditions, neural stem cells can either be in a resting, quiescent state, or they can be actively dividing [23,28,29]. Proliferating stem cells are capable of continuous self-renewal through mitotic cell division, and can differentiate into a number of different cell types, such as neurons, astrocytes and oligodendrocytes.…”

Section: Adult Hippocampal Neurogenesismentioning

confidence: 99%

The role of the N-methyl-d-aspartate receptor in the proliferation of adult hippocampal neural stem and precursor cells

Taylor

Bartlett

2014

Sci. China Life Sci.

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New neurons are continuously generated from resident pools of neural stem and precursor cells (NSPCs) in the adult brain. There are multiple pathways through which adult neurogenesis is regulated, and here we review the role of the N-methyl-D-aspartate receptor (NMDAR) in regulating the proliferation of NSPCs in the adult hippocampus. Hippocampal-dependent learning tasks, enriched environments, running, and activity-dependent synaptic plasticity, all potently up-regulate hippocampal NSPC proliferation. We first consider the requirement of the NMDAR in activity-dependent synaptic plasticity, and the role the induction of synaptic plasticity has in regulating NSPCs and newborn neurons. We address how specific NMDAR agonists and antagonists modulate proliferation, both in vivo and in vitro, and then review the evidence supporting the hypothesis that NMDARs are present on NSPCs. We believe it is important to understand the mechanisms underlying the activation of adult neurogenesis, given the potential that endogenous stem cell populations have for repopulating the hippocampus with functional new neurons. In conditions such as age-related memory decline, neurodegeneration and psychiatric disease, mature neurons are lost or become defective; as such, stimulating adult neurogenesis may provide a therapeutic strategy to overcome these conditions. The adult brain continuously generates new neurons throughout life. These adult-born neurons arise from endogenous neural stem and precursor cells (NSPCs), which primarily reside within two neurogenic niches: the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus, and the subventricular zone (SVZ) of the lateral ventricles. In the 20 years since adult mammalian neurogenesis started receiving substantial attention [1,2], scientists have made great progress in understanding the mechanisms that regulate stem cell maintenance, proliferation, differentiation, maturation and integration [3,4]. Early on, extrinsic cues from the environment, such as learning [5], physical activity [6], and enriched environments [7,8], were found to potently enhance hippocampal neurogenesis. It was not long before a link was made to synaptic plasticity [9], which is also enhanced by physical exercise [10], and is widely accepted as the synaptic mechanism underlying hippocampal learning and memory [11]. Synaptic plasticity and adult hippocampal neurogenesis are intimately linked, as long-term potentiation (LTP), an activity-dependent change in synaptic efficacy, can influence the activation and proliferation of NSPCs in the DG (e.g., [12]), as well as the survival of newborn neurons (e.g., [13]). These newborn neurons have biophysical characteris-

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In Vivo Clonal Analysis Reveals Self-Renewing and Multipotent Adult Neural Stem Cell Characteristics

Cited by 767 publications

References 54 publications

Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors

Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors

Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

The role of the N-methyl-d-aspartate receptor in the proliferation of adult hippocampal neural stem and precursor cells

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