Local generation of glia is a major astrocyte source in postnatal cortex
Howard Hughes Medical Institute, Department of Physiology, University of California at San Francisco, 1550 4th Street, San Francisco, California 94158, USA.Nature (Impact Factor: 41.46). 03/2012; 484(7394):376-80. DOI: 10.1038/nature10959
Glial cells constitute nearly 50% of the cells in the human brain. Astrocytes, which make up the largest glial population, are crucial to the regulation of synaptic connectivity during postnatal development. Because defects in astrocyte generation are associated with severe neurological disorders such as brain tumours, it is important to understand how astrocytes are produced. Astrocytes reportedly arise from two sources: radial glia in the ventricular zone and progenitors in the subventricular zone, with the contribution from each region shifting with time. During the first three weeks of postnatal development, the glial cell population, which contains predominantly astrocytes, expands 6-8-fold in the rodent brain. Little is known about the mechanisms underlying this expansion. Here we show that a major source of glia in the postnatal cortex in mice is the local proliferation of differentiated astrocytes. Unlike glial progenitors in the subventricular zone, differentiated astrocytes undergo symmetric division, and their progeny integrate functionally into the existing glial network as mature astrocytes that form endfeet with blood vessels, couple electrically to neighbouring astrocytes, and take up glutamate after neuronal activity.
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[Show abstract] [Hide abstract] ABSTRACT: Astrocytes maintain the homeostasis of the central nervous system (CNS) by e.g. recycling of neurotransmitters and providing nutrients to neurons. Astrocytes function also as key regulators of synaptic plasticity and adult neurogenesis. Any insult to the CNS tissue triggers a range of molecular, morphological and functional changes of astrocytes jointly called reactive (astro)gliosis. Reactive (astro)gliosis is highly heterogeneous and also context-dependent process that aims at the restoration of homeostasis and limits tissue damage. However, under some circumstances, dysfunctional (astro)gliosis can become detrimental and inhibit adaptive neural plasticity mechanisms needed for functional recovery. Understanding the multifaceted and context-specific functions of astrocytes will contribute to the development of novel therapeutic strategies that, when applied at the right time-point, will improve the outcome of diverse neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
- "After injury in the brain cortex, the majority of astrocytes undergo cellular hypertrophy, upregulate GFAP, but they stay within their respective tiled domains with only a limited overlap between domains of adjacent astrocytes  , while some astrocytes become polarized , and some proliferate, in particular those associated with blood vessels . It is interesting to point out the similarities between the reaction of cortical astrocytes to injury and astrocytes in earlier ontogenic stages that also proliferate but do not migrate  . It seems that these proliferating blood vessel-associated astrocytes control the migration and proliferation of glial scar forming pericytes  . "
[Show abstract] [Hide abstract] ABSTRACT: The mammalian neocortex is composed of two major neuronal cell types with distinct origins: excitatory pyramidal neurons and inhibitory interneurons, generated in dorsal and ventral progenitor zones of the embryonic telencephalon, respectively. Thus, inhibitory neurons migrate relatively long distances to reach their destination in the developing forebrain. The role of lineage in the organization and circuitry of interneurons is still not well understood. Utilizing a combination of genetics, retroviral fate mapping, and lineage-specific retroviral barcode labeling, we find that clonally related interneurons can be widely dispersed while unrelated interneurons can be closely clustered. These data suggest that migratory mechanisms related to the clustering of interneurons occur largely independent of their clonal origin. Copyright © 2015 Elsevier Inc. All rights reserved.
- "Most cells were located hundreds or thousands of microns from their nearest identified sibling cell (Figures 4A and 4D). The only observed pair of clonally related cells located in the same 25-mm thick brain section was a pair of glia in the septum, consistent with previous findings of local proliferation of glial progenitor cells (Figure 4D, Clone 16) (Ge et al., 2012). We examined the nearest neighbor distribution of retrovirus-labeled GFP-positive cells by assigning coordinates to each cell during serial section reconstruction and categorizing cells as sibling members of a multi-cell clone, unrelated clones, or cells that did not return a barcode sequence (unknown lineage) (Figure 4D; Table S1). "
[Show abstract] [Hide abstract] ABSTRACT: Direct lineage reprogramming induces dramatic shifts in cellular identity, employing poorly understood mechanisms. Recently, we demonstrated that expression of Neurog2 or Ascl1 in postnatal mouse astrocytes generates glutamatergic or GABAergic neurons. Here, we take advantage of this model to study dynamics of neuronal cell fate acquisition at the transcriptional level. We found that Neurog2 and Ascl1 rapidly elicited distinct neurogenic programs with only a small subset of shared target genes. Within this subset, only NeuroD4 could by itself induce neuronal reprogramming in both mouse and human astrocytes, while co-expression with Insm1 was required for glutamatergic maturation. Cultured astrocytes gradually became refractory to reprogramming, in part by the repressor REST preventing Neurog2 from binding to the NeuroD4 promoter. Notably, in astrocytes refractory to Neurog2 activation, the underlying neurogenic program remained amenable to reprogramming by exogenous NeuroD4. Our findings support a model of temporal hierarchy for cell fate change during neuronal reprogramming. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
- "As astrocytes at postnatal stages are still plastic and proliferate (Ge et al., 2012; Laywell et al., 2000), we tested how reprogramming would be affected if astrocytes were cultured for a longer time. To this end, we maintained Neurog2ERT2-transduced murine astroglial cells in culture for 6 or 8 extra days (data not shown) before starting OHT treatment for 6 days (Figure 5A; condition is referred to as ''delayed induction'' or prolonged culture [6 days after passaging], while the condition described in Figure 1A is referred to as ''early induction'' [1–2 days after passaging]). "