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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    • "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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    • "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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