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
Source: PubMed


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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    • "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). "
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    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.
    Neuron 08/2015; 87(5). DOI:10.1016/j.neuron.2015.07.030 · 15.05 Impact Factor
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    • "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]). "
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    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.
    Cell stem cell 06/2015; 17(1). DOI:10.1016/j.stem.2015.05.014 · 22.27 Impact Factor
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    • "It will also be essential to better characterize progenitor types and their proliferation patterns in astrocyte lineages. The transitamplifying intermediate astrocyte precursors observed in the spinal cord and possibly the cerebral cortex (Ge et al. 2012; Tien et al. 2012) could potentially undergo temporal patterning to expand astrocyte heterogeneity in the CNS (Bayraktar and Doe 2013). Finally, it will also be important to consider that some astrocyte functions also change over time. "
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    ABSTRACT: Astrocytes have many roles within the brain parenchyma, and a subpopulation restricted to germinal niches function as neural stem cells (NSCs), that produce various types of neuronal progeny in relation to spatiotemporal factors. A growing body of evidence supports the concept of morphological and molecular differences between astrocytes in different brain regions, which might relate to their derivation from regionally patterned radial glia. Indeed, the notion that astrocytes are molecularly and functionally heterogeneous could help explain how the central nervous system (CNS) retains embryonic positional information into adulthood. Here, we discuss recent evidence for regionally encoded functions of astrocytes in the developing and adult CNS to provide an integrated concept of the origin and possible function of astrocyte heterogeneity. We focus on the regionalization of NSCs in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain and emerging evidence for a segmental organization of astrocytes in the developing spinal cord and forebrain. We propose that astrocytes' diversity will provide fundamental clues to understand regional brain organization and function. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 11/2014; 7(1). DOI:10.1101/cshperspect.a020362 · 8.68 Impact Factor
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