Local production of astrocytes in the cerebral cortex

“Individual radial glia began to transform into astrocytes after they completed neurogenesis in late embryonic stages (Noctor et al., 2004).”

“They have radially oriented long processes spanning the entire cortical wall in the human fetal cortex and spinal cord (Rakic, 1972; Choi and Lapham, 1978).”

“…some researchers have used Aldh1l1-Cre and GFAP-CreER to label astrocytes after a mouse line is crossed with an appropriate reporter line (Gong et al., 2003; Casper et al., 2007; Chow et al., 2008; Ge et al., 2012; Tien et al., 2012; Please cite this article in press as: Ge W-P, Jia J-M.”

“It is well established that NG2 glia have the potential to produce both oligodendrocytes and astrocytes in vitro (Raff et al., 1983).”

“, lacZ or EGFP) into the genome of dividing cells (Turner and Cepko, 1987).”

“NG2 glia account for 5–8% of the glial population (Levine et al., 2001) and form synapses with neurons (Bergles et al., 2000; Lin and Bergles, 2004).”

“They administrated tamoxifen at P4, P30, P45, and P180 and then analyzed the progeny after days or months to analyze whether NG2 glia produced astrocytes in the postnatal brain (Rivers et al., 2008; Kang et al., 2010; Clarke et al., 2012).”

“Although cell proliferation outside the SVZ and VZ is quite rare in the adult brain, cell division in glia occurs in nearly all major rodent brain regions including the cerebral cortex, corpus callosum, stratum, hypothalamus, and septum (Messier et al., 1958; Walker and Leblond, 1958; Hain et al., 1961; Smart and Lebl…”

“They administrated tamoxifen at P4, P30, P45, and P180 and then analyzed the progeny after days or months to analyze whether NG2 glia produced astrocytes in the postnatal brain (Rivers et al., 2008; Kang et al., 2010; Clarke et al., 2012).”

“These glia are the major dividing cells in the nervous system outside of neurogenic regions in the adult rodent brain (Levine et al., 1993; Horner et al., 2000; Dawson et al., 2003; Kukley et al., 2008; Ge et al., 2009; Geha et al., 2010).”

“A similar phenomenon was also reported in glial clusters by labeling SVZ cells with two retroviruses at extremely low multiplicity of infection that expressed two different markers to ensure that each cluster of cells was derived from an individual cell after its progeny migrated into the rat cerebral cortex (Levison…”

“In the early embryonic stage of rhesus monkey, transitional radial glia detach from the ventricle surface with a long process terminating at blood vessels during the first half of gestation (Schmechel and Rakic, 1979; Levitt and Rakic, 1980).”

“…al. (1993) Retroviral labeling Rat Levison and Goldman (1993) Retroviral labeling Mouse Marshall and Goldman (2002) NG2 glia Genetic tracing Mouse Zhu et al. (2008) Genetic tracing Mouse Guo et al. (2009) Locally proliferating glia Radioautography Rat Kaplan and Hinds (1980) Retroviral labeling…”

“…and Thurlow (1988) Retroviral labeling Rat Levison and Goldman (1993) Organotypic slice culture and time-lapse imaging Mouse Burns et al. (2009) In vivo imaging, retroviral labeling, and genetic tracing Mouse Ge et al. (2012) Genetic tracing Mouse Magavi et al. (2012) (Schmechel and Rakic, 1979).”

“NG2 glia account for 5–8% of the glial population (Levine et al., 2001) and form synapses with neurons (Bergles et al., 2000; Lin and Bergles, 2004).”

“Clusters with large numbers of glia labeled with [3H]thymidine (with subsequent visualization via autoradiography) could be observed in the cerebral cortex of both young adult rat and cat brains (Altman, 1963).”

“Sources of astrocytes in the cerebral cortex Sources Methods Species References Radial glia Golgi staining Monkey Schmechel and Rakic (1979) Labeling with DiI Ferret Voigt (1989) Labeling with dyes (DiI/DiA) Human (fetus) deAzevedo et al. (2003) Organotypic slice cultures and time-lapse imaging Rat Noctor et al. (2004…”

“Sources of astrocytes in the cerebral cortex Sources Methods Species References Radial glia Golgi staining Monkey Schmechel and Rakic (1979) Labeling with DiI Ferret Voigt (1989) Labeling with dyes (DiI/DiA) Human (fetus) deAzevedo et al. (2003) Organotypic slice cultures and time-lapse imaging Rat Noctor et al. (2004…”

“…and Thurlow (1988) Retroviral labeling Rat Levison and Goldman (1993) Organotypic slice culture and time-lapse imaging Mouse Burns et al. (2009) In vivo imaging, retroviral labeling, and genetic tracing Mouse Ge et al. (2012) Genetic tracing Mouse Magavi et al. (2012) (Schmechel and Rakic, 1979).”

“In such columns, 70% of neurons were projection neurons (Jones, 1993; Wonders and Anderson, 2005).”

“Astrocytes are the largest glial population in the mammalian brain, and most astrocytes are produced postnatally (Sauvageot and Stiles, 2002; Freeman, 2010).”

“Abundant evidence has shown that SVZ progenitors produce both astrocytes and oligodendrocytes in the postnatal rodent cerebral cortex (Smart, 1961; Lewis, 1968; Privat and Leblond, 1972; Paterson et al., 1973; Paterson, 1983; Levison and Goldman, 1993; Levison et al., 1993; Marshall and Goldman,…”

“NG2 glia account for 5–8% of the glial population (Levine et al., 2001) and form synapses with neurons (Bergles et al., 2000; Lin and Bergles, 2004).”

“To date, the efficient way of identifying cortical astrocytes is to fluorescently label them by expressing an exogenous gene such as GFAP-GFP (Zhuo et al., 1997; Matthias et al., 2003) or Aldh1L1-GFP (Heintz, 2001) under control of the respective promoter.”

“Glial number in the cortex increases sixfold to eightfold from four to six million during postnatal (P) days 1–6 to 35 million at P21 and remains stable throughout adulthood (Bandeira et al., 2009).”

“Astrocytes are the largest glial population in the mammalian brain, and most astrocytes are produced postnatally (Sauvageot and Stiles, 2002; Freeman, 2010).”

“To date, the efficient way of identifying cortical astrocytes is to fluorescently label them by expressing an exogenous gene such as GFAP-GFP (Zhuo et al., 1997; Matthias et al., 2003) or Aldh1L1-GFP (Heintz, 2001) under control of the respective promoter.”

“Radial glia were originally discovered by Camillo Golgi in 1885 (Rakic, 2003).”

“, 2003) or Aldh1L1-GFP (Heintz, 2001) under control of the respective promoter.”

“Plp promoter activity is restricted to the oligodendrocyte lineage (Doerflinger et al., 2003).”

“These glia are the major dividing cells in the nervous system outside of neurogenic regions in the adult rodent brain (Levine et al., 1993; Horner et al., 2000; Dawson et al., 2003; Kukley et al., 2008; Ge et al., 2009; Geha et al., 2010).”

“Although cell proliferation outside the SVZ and VZ is quite rare in the adult brain, cell division in glia occurs in nearly all major rodent brain regions including the cerebral cortex, corpus callosum, stratum, hypothalamus, and septum (Messier et al., 1958; Walker and Leblond, 1958; Hain et al., 1961; Smart and Lebl…”

“They have radially oriented long processes spanning the entire cortical wall in the human fetal cortex and spinal cord (Rakic, 1972; Choi and Lapham, 1978).”

“…infection Mouse Tsai et al. (2012) SVZ progenitors Radioautography Mouse Smart (1961) Radioautography Rat Lewis (1968) Radioautography Rat Paterson et al. (1973) Radioautography Mouse Paterson (1983) Retroviral labeling Rat Levison et al. (1993) Retroviral labeling Rat Levison and…”

“…has shown that SVZ progenitors produce both astrocytes and oligodendrocytes in the postnatal rodent cerebral cortex (Smart, 1961; Lewis, 1968; Privat and Leblond, 1972; Paterson et al., 1973; Paterson, 1983; Levison and Goldman, 1993; Levison et al., 1993; Marshall and Goldman, 2002; Burns…”

“Shortly after birth, many axons pass through the white matter in the rodent forebrain (Wang et al., 2007; Zhou et al., 2013) and likely form a physical barrier to astrocyte migration after disappearance of radial glia; moreover, the number of SVZ progenitor–derived astrocytes that migrate into the cortex with assistan…”

“Dividing astrocytes mainly contribute to the first peak (Ge et al., 2012), and dividing NG2 glia mainly contribute to the second peak (Levison et al., 1993; Zerlin et al., 1995; Parnavelas, 1999; Kukley et al., 2008; Ge et al., 2009, 2012).”

“They administrated tamoxifen at P4, P30, P45, and P180 and then analyzed the progeny after days or months to analyze whether NG2 glia produced astrocytes in the postnatal brain (Rivers et al., 2008; Kang et al., 2010; Clarke et al., 2012).”

“Cell proliferation in the cortex has been reported for over a century in different species including dogs, cats, rats, and mice (Buchholtz, 1890; Sclavunos, 1899; Hamilton, 1901; Addison, 1911; Allen, 1912).”

“…glia Golgi staining Monkey Schmechel and Rakic (1979) Labeling with DiI Ferret Voigt (1989) Labeling with dyes (DiI/DiA) Human (fetus) deAzevedo et al. (2003) Organotypic slice cultures and time-lapse imaging Rat Noctor et al. (2004) Organotypic slice cultures and time-lapse imaging…”

“Abundant evidence has shown that SVZ progenitors produce both astrocytes and oligodendrocytes in the postnatal rodent cerebral cortex (Smart, 1961; Lewis, 1968; Privat and Leblond, 1972; Paterson et al., 1973; Paterson, 1983; Levison and Goldman, 1993; Levison et al., 1993; Marshall and Goldman,…”

“Local production of as 10.1016/j.neuroscience.2015.08.057 Voigt, 1989; Gressens et al., 1992; Noctor et al., 2004).”

“These glia are the major dividing cells in the nervous system outside of neurogenic regions in the adult rodent brain (Levine et al., 1993; Horner et al., 2000; Dawson et al., 2003; Kukley et al., 2008; Ge et al., 2009; Geha et al., 2010).”

“In glia, DNA synthesis during S-phase lasts 10 h (Korr et al., 1973), and the subsequent G2 lasts 2–3 h (Hommes and Leblond, 1967; Korr et al., 1973).”

“9% were from NG2 glia in these mice (Guo et al., 2009).”

“Dividing astrocytes mainly contribute to the first peak (Ge et al., 2012), and dividing NG2 glia mainly contribute to the second peak (Levison et al., 1993; Zerlin et al., 1995; Parnavelas, 1999; Kukley et al., 2008; Ge et al., 2009, 2012).”

“Although cell proliferation outside the SVZ and VZ is quite rare in the adult brain, cell division in glia occurs in nearly all major rodent brain regions including the cerebral cortex, corpus callosum, stratum, hypothalamus, and septum (Messier et al., 1958; Walker and Leblond, 1958; Hain et al., 1961; Smart and Lebl…”

“Shortly after birth, many axons pass through the white matter in the rodent forebrain (Wang et al., 2007; Zhou et al., 2013) and likely form a physical barrier to astrocyte migration after disappearance of radial glia; moreover, the number of SVZ progenitor–derived astrocytes that migrate into the cortex with assistan…”

“Abundant evidence has shown that SVZ progenitors produce both astrocytes and oligodendrocytes in the postnatal rodent cerebral cortex (Smart, 1961; Lewis, 1968; Privat and Leblond, 1972; Paterson et al., 1973; Paterson, 1983; Levison and Goldman, 1993; Levison et al., 1993; Marshall and Goldman, 2002; Burns et al., 20…”

“Dividing astrocytes mainly contribute to the first peak (Ge et al., 2012), and dividing NG2 glia mainly contribute to the second peak (Levison et al., 1993; Zerlin et al., 1995; Parnavelas, 1999; Kukley et al., 2008; Ge et al., 2009, 2012).”

“…some researchers have used Aldh1l1-Cre and GFAP-CreER to label astrocytes after a mouse line is crossed with an appropriate reporter line (Gong et al., 2003; Casper et al., 2007; Chow et al., 2008; Ge et al., 2012; Tien et al., 2012; Please cite this article in press as: Ge W-P, Jia J-M.”

“Dividing astrocytes can be identified via electron microscopy after [3H]thymidine labeling (Kaplan and Hinds, 1980; Reyners et al., 1986).”

“Dividing astrocytes mainly contribute to the first peak (Ge et al., 2012), and dividing NG2 glia mainly contribute to the second peak (Levison et al., 1993; Zerlin et al., 1995; Parnavelas, 1999; Kukley et al., 2008; Ge et al., 2009, 2012).”

“Themean percentage of dividing cells at four ages (at age 23, 100, 200, and 400 days) in mouse brain was determined to be: 0.142% in the septum, 0.445% in the corpus callosum, 0.048% in the corpus stratum, 0.058% in the hypothalamus and 0.090% in the cerebral cortex (Dalton et al., 1968).”

“In glia, DNA synthesis during S-phase lasts 10 h (Korr et al., 1973), and the subsequent G2 lasts 2–3 h (Hommes and Leblond, 1967; Korr et al., 1973).”

“…and Thurlow (1988) Retroviral labeling Rat Levison and Goldman (1993) Organotypic slice culture and time-lapse imaging Mouse Burns et al. (2009) In vivo imaging, retroviral labeling, and genetic tracing Mouse Ge et al. (2012) Genetic tracing Mouse Magavi et al. (2012) (Schmechel and Rakic, 1979).”

“Although cell proliferation outside the SVZ and VZ is quite rare in the adult brain, cell division in glia occurs in nearly all major rodent brain regions including the cerebral cortex, corpus callosum, stratum, hypothalamus, and septum (Messier et al., 1958; Walker and Leblond, 1958; Hain et al., 1961; Smart and Lebl…”

“Cell proliferation in the cortex has been reported for over a century in different species including dogs, cats, rats, and mice (Buchholtz, 1890; Sclavunos, 1899; Hamilton, 1901; Addison, 1911; Allen, 1912).”

“Sources of astrocytes in the cerebral cortex Sources Methods Species References Radial glia Golgi staining Monkey Schmechel and Rakic (1979) Labeling with DiI Ferret Voigt (1989) Labeling with dyes (DiI/DiA) Human (fetus) deAzevedo et al. (2003) Organotypic slice cultures and time-lapse imaging Rat Noctor et al. (2004…”

“…some researchers have used Aldh1l1-Cre and GFAP-CreER to label astrocytes after a mouse line is crossed with an appropriate reporter line (Gong et al., 2003; Casper et al., 2007; Chow et al., 2008; Ge et al., 2012; Tien et al., 2012; Please cite this article in press as: Ge W-P, Jia J-M.”

“In such columns, 70% of neurons were projection neurons (Jones, 1993; Wonders and Anderson, 2005).”

“In addition, the density of glia in the juvenile cat cortex increases by 60% upon reaching adulthood, and then it increases slightly thereafter (Brizzee and Jacobs, 1959).”

“Dividing astrocytes can be identified via electron microscopy after [3H]thymidine labeling (Kaplan and Hinds, 1980; Reyners et al., 1986).”

“There are two peaks of local proliferation of glia in the rat cerebral cortex after birth: the first is at P3–7, and the second is at P16 (Allen, 1912; Ichikawa et al., 1983).”

“…does not appear to determine its radial position, and (2) some astrocytes will divide symmetrically to locally produce more astrocytes, a process that continues into adulthood (Ge and Jia, 2016); and (3) a subpopulation of cortical astrocytes appear to be derived from NG2+ cells (Zhu et al., 2008).”

“In the healthy postnatal cortex, it has been shown that local proliferation of astrocytes, not NG2 glia, account for a majority of the astrocyte population (Ge et al., 2012; Ge and Jia, 2016).”

“In the cerebral cortex, astrocytes are produced from radial glial cells in humans, and also from progenitors in the subventricular zone, locally proliferating glia and NG2 glia (Ge & Jia, 2016) in rodents.”

“In contrast, brain-derived glial cells, including oligodendrocyte precursor cells (OPC) (16) and astrocytes to a lower extent (17), retain the ability to proliferate in the postnatal brain.”

“In fact, after birth, the glial cells in the rodent brain expand six- to eightfold, with local sources, presumably radial glia, providing the initial glial pool.(110,111) During astrogliogenesis in vivo, radial glial cells progressively lose nestin and RC2 immunoreactivities and acquire a more ramified appearance and…”

“Newly born astrocytes migrate along radial glial cell processes to different cortical layers and undergo local division (Ge and Jia, 2016).”

“zone progenitor cells, NG2 glia and local proliferation remain unavailable [48].”

“Whereas neuronal cells are highly differentiated and postmitotic cells, mature astrocytes in the brain are capable of cell proliferation [82,83].”

“Unlike neurons, astrocytes maintain the capacity of cell division, and new astrocytes are continuously generated in many regions during postnatal development [63].”

“Glia generation was determined at the early neonatal stage P3 when the local proliferation of glia had not fully begun (23).”

“From a therapeutic point of view, unlike neurons, which barely duplicate in the adult brain, astrocytes and glia maintain their capability for duplication [24].”

“It possess a rich source, such as neural progenitors cell in the subventricular zone (SVZ) of the lateral ventricles, oligodendrocyte precursor cells (OPCs) that comprise 5 – 8% of glial cells and radial glia after completion of neurogenesis (Ge & Jia, 2016).”

“Our use of Bac slc1a3-CreER transgenic mice and the 4-OHT administration paradigm (P4-P9 injections) for generating astroglial Fmr1 cKO and cON mice leads to highly specific Fmr1 deletion in astroglia as radial glial cells in which the slc1a3 promoter is also active are all destined to differentiate into astroglia dur…”

“Neuritic arborization begins in postnatal developmental stages and in the brain regions that have generated functional astrocytes [47].”

“Astrocytes produced by progenitor cells in the SVZ are thought to migrate like neurons, through attachment to radial glial cells.(88) Recent work has found that YAP is expressed in cortical astrocytes and appears to play a role in astrocyte differentiation, as differentiation capacity is decreased in cultured YAP1658…”

“These results are partially consistent with the previous study which showed adult NPCs from Fmr1 KO mice had increased protein expression of CDK4 and cyclin D1 compared with that of WT mice (Luo et al., 2010).”

“The dividing glial cells transfected with the CAG::NeuroD1-P2A-GFP retrovirus in the mouse cortex were actually quite rare ( 1%), consistent with a previous report of only a small population of dividing glial cells in adult mouse brains (Ge and Jia, 2016).”

“Currently, there is evidence that radial glia, neuronal progenitor cells (NPCs) within the subventricular (SVZ) and subgranular (SGZ) zones, locally proliferating glia, in addition to NG2+ cells may all contribute to newly generated pools of reactive astrocytes after injury [56].”

“The main microstructural changes that occur in the hypoxic cerebral are impaired dendritic arborization of neurons (37) and inhibition of glial cell formation (35, 38, 39).”

“However, during the first two post-natal weeks and decreasing with age the SVZ retains the capacity to produce CR+ interneurons contributing to the pools of GABAergic neurons mainly populating lower cortical layers and cingulate cortex [90–92].”

“Cortical astrocytes are capable of self-renewal throughout the human lifespan [22, 24, 25] and dysregulation of the cell cycle could result in tumorigenesis on one end of the spectrum, while aged atrophied senescent mature astrocytes incapable of reentering the cell cycle could result in neurodegenerative disease on t…”

“These findings are consistent with previous reports, showing that astrocytic populations in the cerebral cortex are higher in the mature than in the developing brain (Ge & Jia, 2016).”

“Astrocyte generation occurs continuously in the adult brain through a heterogeneous process involving both NSC-derived newborn astrocytes and the re-entry of parenchymal astrocytes into the cell cycle (Ge & Jia, 2016 ).”

“At that point in time, they aid neurons’ migration by acting as scaffolds [10].”

“Radial glia translocate from the lateral VZ and become immature astrocytes in the cortex during the late embryonic or early postnatal phase [11, 37].”

“Therefore, as human cortical astrocytes are expressing γ-syn within non-pathological conditions this could possibly provide a mechanism to exhibit its proliferative abilities in order to progress normally through the cell cycle (Guizzetti et al., 2011; Ge and Jia, 2016).”

“During this period, already differentiated cells divide; because of this, approximately half of the entire population of astrocytes in the central nervous system arises (Bandeira et al., 2009; Ge and Jia, 2016).”

“Concurrently, glial cells undergo proliferation in this timeframe to exhibit a six-to eight-fold increase (Ge & Jia, 2016 ; Majcher-Maślanka et al., 2019).”