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Cited by 874Neurogenesis and neuroplasticity mechanismsMultiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration Mechanisms

Oligodendrocyte Dynamics in the Healthy Adult CNS: Evidence for Myelin Remodeling

Open access
Young, Kaylene M., Psachoulia, Konstantina, Tripathi, Richa B., Dunn, Sara-Jane, Cossell, Lee, Attwell, David, Tohyama, Koujiro, Richardson, William D.·2013·Neuron
DOI 10.1016/j.neuron.2013.01.006PMC PMC3842597
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Abstract

Oligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood. It is not known whether adult-born OLs ensheath previously unmyelinated axons or remodel existing myelin. We quantified OP division and OL production in different regions of the adult mouse CNS including the 4-month-old optic nerve, in which practically all axons are already myelinated. Even there, all OPs were dividing and generating new OLs and myelin at a rate higher than can be explained by first-time myelination of naked axons. We conclude that adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths. The latter would predict that average internode length should decrease with age. Consistent with that, we found that adult-born OLs elaborated much shorter but many more internodes than OLs generated during early postnatal life.

AI snapshot

Written from the paper’s full text.

TL;DR

Adult mouse oligodendrocyte precursors continue dividing and generating new oligodendrocytes even in the almost fully myelinated optic nerve. Adult-born oligodendrocytes elaborate many more, shorter internodes than early-born oligodendrocytes, suggesting myelin remodeling rather than only de novo myelination.

Key findings

  • All OPs were cycling throughout the adult CNS (growth fraction ≈100%), with cell-cycle time depending on region and age: at P60, ~10 days in corpus callosum, ~15 days in spinal cord white matter, ~20 days in optic nerve, and ~36 days in cortical gray matter.
  • In optic nerve, ~6.5% ± 1.5% of CC1+ oligodendrocytes at P185 were born after P120, far exceeding the ~1% of axons still unmyelinated, implying adult-born OLs are engaged in myelin remodeling.
  • Late-born OLs (P120–P185) had 77 ± 7 internodes per OL of mean length 22 ± 1 μm, whereas early-born OLs (P30–P60) had 21 ± 7 internodes of mean length 76 ± 2 μm; total myelin length per cell was similar (~1,700 μm vs. ~1,600 μm).
  • Newly formed myelin after P120 had a slightly higher g-ratio (0.75 ± 0.06) than myelin formed after P30 (0.72 ± 0.05), and >94% of examined mGFP+ internodes were Caspr+.

Methods

  • Used cumulative EdU labeling and Pdgfra-CreERT2 fate mapping with R26R-YFP or Tau-mGFP reporters in postnatal and adult mice, including tamoxifen administration at P45, P60, and P120.
  • Quantified OP labeling index, cell-cycle time, OL differentiation, internode number/length by confocal microscopy, and myelin morphology/g-ratio by immunoelectron microscopy.
  • Conducted simulations of conduction speed based on previously published models.

Limitations

  • The paper states that survival calculations have considerable uncertainty concerning the rate of increase of cell-cycle time with age and may underestimate the proportion of new OLs that survive; it also states that it is not yet known whether significant OL or myelin turnover occurs during the first year of life in mice.
  • Evident from the text: conclusions are based on mouse CNS regions, primarily optic nerve, corpus callosum, spinal cord, and cortex, so generalization to other species or regions is not established.
  • Evident from the text: tamoxifen recombination labels only a subset of OPs (~20% in optic nerve; ~4% in Tau-mGFP optic nerves), and internode counts required a sampling correction because section thickness was less than the OL process field diameter.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2013.01.006

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 48 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In the 4-month-old mouse optic nerve, practically all axons are already myelinated.

    “We quantified OP division and OL production in different regions of the adult mouse CNS including the 4-month-old optic nerve, in which practically all axons are already myelinated.”
    • Also stated in: § Introduction · plain
      “which consists almost entirely of myelinated axons (Honjin et al., 1977; Bartsch et al., 1997; Dangata and Kaufman, 1997)”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Honjin et al., 1977 source

      The Summary reports that 98.8% of optic nerve fibers were myelinated, supporting “practically all.” But Material and Methods identifies the studied mice as 6–8 months old, not 4 months old. The Discussion mentions a separate count of myelinated fibers at 4 months without establishing what proportion of axons were myelinated then. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites Bartsch et al., 1997 source
    • cites Dangata and Kaufman, 1997 source
  • Findingcitation

    For every day after birth, TC in cortical gray matter increases by about two-thirds of a day, not one-third as previously estimated.

    “This remarkable conclusion still stands, although the rate of increase with time is greater than previously estimated: for every day after birth, TC in the cortical gray matter increases by about two-thirds of a day, not one-third as previously estimated (Psachoulia et al., 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Psachoulia et al., 2009 source

      The Discussion (page unavailable) reports cortical NG2-cell cycle time increasing from about 2 days at P6 to more than 150 days at P240, consistent with an average increase of roughly two-thirds of a day per day over that interval. The paper does not state that this rate holds for every day after birth or identify a previous one-third-of-a-day estimate. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingcitation

    TC in cortical gray matter increases linearly with age from early postnatal ages until at least P540.

    “We reported previously that TC in the cortical gray matter increases linearly with age from early postnatal ages until at least P540 (Psachoulia et al., 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Psachoulia et al., 2009 source

      The Results section, “The NG2 cell cycle slows dramatically with age” (page unavailable), reports that cortical NG2-cell cycle time increased steadily from about 2 days at P6 to more than 100 days at P540. It does not establish a linear increase, and it says the P540 value cannot be determined confidently because the growth fraction is unknown. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Approximately 30% of all OLs present in the corpus callosum of 8-month-old mice are generated after 7 weeks of age.

    “The scale of new OL genesis in the adult is unexpectedly large: ∼30% of all OLs present in the corpus callosum of 8-month-old mice are generated after 7 weeks of age (Rivers et al., 2008; Zhu et al., 2011).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Rivers et al., 2008 source
    • cites Zhu et al., 2011 source

      The Results and Discussion (page numbers not supplied) estimate that 30% of corpus-callosum oligodendrocytes in P120 mice were generated from NG2 cells between P60 and P120. This supports the approximate proportion but not the claim's ages: the paper measures mice at about 4 months, not 8 months, and begins tracking at P60, not 7 weeks. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Interpretationreasoning

    There is a large disparity between the proportion of new myelin laid down in the optic nerve after P120 (approximately 6.5% of the total) and the proportion of axons that remains unmyelinated at that time (approximately 1%).

    “As shown in the following section, the total length of myelin sheath that is synthesized by adult-born OLs is similar to that synthesized by early-born OLs, so there is a large disparity between the proportion of new myelin that is laid down in the optic nerve after P120 (∼6.5% of the total) and the proportion of axons that remains unmyelinated at that time (∼1%) (Honjin et al., 1977; Dangata et a”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Honjin et al., 1977 source
    • cites Dangata et al., 1996

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims. 34
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Premisecitation

    Oligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood.

    “Oligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood.”
    • Also stated in: § Introduction · plain
      “However, OPs continue to divide and generate new-myelinating OLs well into adulthood (Dimou et al., 2008; Rivers et al., 2008; Psachoulia et al., 2009; Kang et al., 2010; Zhu et al., 2011; reviewed by Richardson et al., 2011).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Dimou et al., 2008 source

      The ‘Adult generation of mature oligodendrocytes in the WM’ section reports continued generation of myelinating oligodendrocytes in adult mouse cortical white matter, including at six months. The ‘Mechanisms mediating distinct progeny’ section says gray-matter progenitors proliferate more slowly and that the few oligodendrocytes they generate do not acquire myelinating characteristics. The unqualified claim therefore extends the white-matter finding to oligodendrocyte precursors generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Rivers et al., 2008 source
    • cites Psachoulia et al., 2009 source

  • May combine two claims.

    Interpretationcitation

    Because the number-density of OPs within a given region does not change much with age, half of the daughters of OP divisions must either differentiate or die.

    “Because the number-density of OPs within a given region does not change much with age (Rivers et al., 2008), it follows that half of the daughters of OP divisions must either differentiate (and lose OP markers) or die.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Rivers et al., 2008 source

  • May combine two claims.

    Findingown data

    At P120+7, 19.9% ± 3.2% of all optic nerve OPs (defined by NG2 immunolabeling) were YFP labeled, less than in adult corpus callosum (approximately 45%) or spinal cord (approximately 39%).

    “A short time later (P120+7), 19.9% ± 3.2% of all optic nerve OPs (defined by NG2 immunolabeling) were YFP labeled (mean ±SD, n = 3 mice), less than in the adult corpus callosum (∼45%; Rivers et al., 2008) or spinal cord (∼39%; Zawadzka et al., 2010; Tripathi et al., 2010).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Rivers et al., 2008 source
    • cites Zawadzka et al., 2010 source

      The Results section, “Efficient Labeling of PDGFRA-Expressing Cells after Lysolecithin-Induced Demyelination” (page unavailable), reports approximately 39% YFP labeling in spinal cord precursor cells. That figure is the fraction of PDGFRA-positive cells in a demyelinated lesion, not a measurement of NG2-defined OPs in unlesioned adult spinal cord. This citation does not support the optic-nerve or corpus-callosum figures, which the sentence attributes elsewhere. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Tripathi et al., 2010 source

      The Materials and Methods section (Induction of EAE; page unavailable) reports that about 30% of spinal-cord PDGFRA+ cells became YFP+, compared with about 45–50% in the adult forebrain. This supports the regional comparison but not the cited ∼39% spinal-cord figure, and the paper measures PDGFRA+ rather than NG2-immunolabeled cells for that comparison. The 19.9% optic-nerve result is presented as the citing authors’ own finding, not as a result attributed to Tripathi et al. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    By cumulative labeling with EdU, all OPs throughout the adult CNS can be labeled (GF≈100%), indicating that all OPs are capable of undergoing cell division.

    “Now, by cumulative labeling with EdU (which does not require antigen retrieval), we are able to label all OPs throughout the adult CNS (GF≈100%), indicating that all OPs are capable of undergoing cell division (Clarke et al., 2012; this paper).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Clarke et al., 2012 source

      The Results section reports that cumulative EdU labeling marked >98% of OPCs in the anterior piriform cortex of mice labeled from P60 and concludes that these OPCs are mitotically active. The Methods section also states that EdU detection does not require antigen retrieval. The paper does not establish a growth fraction of approximately 100% throughout the entire adult CNS; its observations concern selected mouse brain regions. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the developing neocortex, approximately 20% of premyelinating OLs die between P7 and P11.

    “In the developing neocortex, ∼20% of premyelinating OLs die between P7 and P11 (Trapp et al., 1997).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Trapp et al., 1997 source

      The Results section reports that approximately 20% of premyelinating oligodendrocytes in the developing cerebral cortex were degenerating at observations between P7 and P21. It does not establish that 20% died specifically between P7 and P11; the Discussion says the incidence of death cannot be determined without knowing how long degeneration remains detectable. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Social conditions experienced by mice can influence the morphological complexity of their OLs (including the number of internodes per OL) and this is mediated by Neuregulin signaling through ErbB3 receptors on OLs.

    “Recently, it has been shown that the social conditions experienced by mice can influence the morphological complexity of their OLs (including the number of internodes per OL) and that this is mediated by Neuregulin signaling through ErbB3 receptors on OLs (Makinodan et al., 2012).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Makinodan et al., 2012 source

      The paper reports that juvenile social isolation produced simpler oligodendrocytes with fewer internodes in the mouse medial prefrontal cortex (main text, Fig. 1; page unavailable). It links these effects to neuregulin-1/ErbB3 signaling, but says that pathway accounts for them 'at least in part' and does not rule out other mechanisms. The claim omits that qualification and the regional and developmental limits of the findings. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Our data are consistent with the observations that abnormally short myelin internodes accumulate with age in mouse spinal cord white matter and that paranode frequency increases with age in the rhesus monkey brain.

    “Our data are consistent with the observations that abnormally short myelin internodes accumulate with age in mouse spinal cord white matter (Lasiene et al., 2009) and that paranode frequency increases with age in the rhesus monkey brain (reviewed by Peters and Kemper, 2012).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Lasiene et al., 2009 source
    • cites Peters and Kemper, 2012 source

  • May combine two claims.

    Premisecitation

    Myelin formed during repair of experimental demyelination or during demyelinating injury or disease is thinner on average (larger g-ratio) than myelin formed during normal development, although this is less pronounced for smaller-diameter axons such as those in the optic nerve.

    “It is well documented that myelin formed during repair of experimental demyelination or during demyelinating injury or disease is thinner on average (larger g-ratio) than myelin that is formed during normal development (e.g., Lasiene et al., 2008), although this is less pronounced for smaller-diameter axons such as those in the optic nerve (Stidworthy et al., 2003).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Lasiene et al., 2008 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Stidworthy et al., 2003 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Simulations published by Lasiene et al. (2009), assuming the existence of a periaxonal space, predicted that shorter internodes should decrease conduction speed.

    “Consistent with this, simulations published by Lasiene et al. (2009), assuming the existence of a periaxonal space, predicted that shorter internodes should decrease conduction speed.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Lasiene et al. (2009) source

      The Discussion says that shorter internodes can change conduction speed and signal timing. It does not say the change is a decrease, and the paper’s internode measurements are not simulations; the searched passages also do not describe an assumed periaxonal space. The claim therefore attributes a more specific prediction and method to this paper than our copy supports. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    At P60+42, 61% ± 3% of YFP+ cells in spinal cord white matter were Pdgfra+ and 41% ± 3% were CC1+.

    “For example, at P60+42, 61% ± 3% of YFP+ cells in the spinal cord white matter were Pdgfra+ and 41% ± 3% were CC1+.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Newly generated mGFP+ OLs in corpus callosum have small, spherical cell bodies with numerous rod-like processes that run parallel to each other in the direction of the axons.

    “At P60+37, mGFP+ cells in the corpus callosum had small, spherical cell bodies with numerous rod-like processes that ran parallel to each other in the direction of the axons (Figure 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The cell-cycle time of OPs in motor cortex gray matter is approximately 19 days at P21 and approximately 36 days at P60.

    “In the gray matter (motor cortex), TC was longer (∼19 days at P21 and ∼36 days at P60) (Figure 1D–1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At P60+42, 61% ± 5% of YFP+ cells in spinal cord gray matter were Pdgfra+ and 34% ± 6% were CC1+.

    “In the spinal cord gray matter, 61% ± 5% were Pdgfra+ and 34% ± 6% were CC1+.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The cell-cycle time (TC) of OPs in corpus callosum is approximately 3 days at P21 and approximately 10 days at P60.

    “In forebrain white matter (corpus callosum), TC was ∼3 days at P21 and ∼10 days at P60 (Figure 1A–1C and 1G; Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At P60, TC is approximately 36 days in cortical gray matter and approximately 27 days in spinal cord gray matter.

    “TC was also longer in P60 cortical gray matter (∼36 days) than in spinal cord gray matter (∼27 days).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In motor cortex, mGFP+ OL processes are less dense, less numerous, and more randomly oriented, but myelin profiles are evident.

    “In the motor cortex, the cell processes were less dense, less numerous, and more randomly oriented but myelin profiles were still evident (Figure 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At P60, TC is approximately 10 days in corpus callosum, approximately 15 days in spinal cord white matter, and approximately 20 days in optic nerve.

    “Cell-cycle time was not the same in all white matter regions; at P60, TC was ∼10 days in corpus callosum, ∼15 days in spinal cord white matter, and ∼20 days in optic nerve (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tandem pairs of mGFP+ internodes were not observed, indicating that individual late-born OLs do not synthesize adjacent internodes along the same axon.

    “Tandem pairs of mGFP+ internodes were not observed, indicating that individual late-born OLs do not synthesize adjacent internodes along the same axon.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no significant differences in either the number of internodes per OL or their average lengths between P50+30 and P50+65.

    “There were no significant differences in either the number of internodes per OL (21 ± 8 at P50+30, 27 ± 6 at P50+65; mean ±SD, n = 10 OLs at each age) or their average lengths (40 ± 3 μm at P50+30, 44 ± 4 μm at P50+65; means ±SEM, n > 140 internodes) (Figure 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TC increases with age not only in cortical gray and white matter but also in spinal cord gray and white matter and in the optic nerve.

    “In the present study, we show that TC increases with age not only in the cortical gray and white matter but also in the spinal cord gray and white matter and in the optic nerve (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All mGFP+ cells were Olig2+, indicating that they were all OL lineage cells.

    “All mGFP+ cells were Olig2+, a few of which were NG2+ (Stallcup and Beasley, 1987), indicating that they were all OL lineage cells (Figure S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No mGFP+ cells in cortex or corpus callosum were NeuN+, suggesting that Pdgfra+ OPs in these regions do not generate neurons.

    “No mGFP+ cells in the cortex or corpus callosum were NeuN+, suggesting that Pdgfra+ OPs in these regions do not generate neurons (Figure S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The recalculated TC in cortical gray matter of P60 mice is approximately 36 days, in close agreement with a recent estimate of approximately 37 days in 2- to 3-month-old mice.

    “For example, we now recalculate TC in the cortical gray matter of P60 mice to be ∼36 days, in close agreement with a recent estimate of ∼37 days in 2- to 3-month-old mice (Simon et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Simon et al., 2011 source

  • May combine two claims.

    Findingown data

    OLs born after P120 elaborated ∼77 internodes per cell of mean length ∼22 μm.

    “OLs born after P120 elaborated ∼77 internodes per cell of mean length ∼22 μm”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In one experiment we counted 144 (GFP+, Caspr+) paranodes, none of which flanked the same node.

    “Since in one experiment we counted 144 (GFP+, Caspr+) paranodes, none of which flanked the same node”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    Transverse (end-on) views of OLs showed that their internodes were distributed more or less uniformly within a cylindrical field centered on the cell soma.

    “Transverse (end-on) views of OLs showed that their internodes were distributed more or less uniformly within a cylindrical field centered on the cell soma.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths.

    “We conclude that adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Axon caliber increases following initial myelination, presumably as a result of myelination.

    “Axon caliber increases following initial myelination, presumably as a result of myelination (Foster et al., 1982), but a further increase in the diameter of myelinated axons over the longer term, as observed here, has not previously been reported for the mouse optic nerve (Dangata et al., 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Foster et al., 1982 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cell-intrinsic differences in the proliferative properties of OPs from different CNS regions have been reported.

    “Cell-intrinsic differences in the proliferative properties of OPs from different CNS regions have also been reported (Power et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Power et al., 2002 source

  • May combine two claims.

    Premisecitation

    In rat optic nerve, the peak time of OL generation is approximately P10-P20 and approximately 85% of axons are myelinated by P28.

    “In the rat optic nerve, the peak time of OL generation is ∼P10–P20 and ∼85% of axons are myelinated by P28 (Skoff et al., 1969).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Skoff et al., 1969 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Approximately 50% of OLs in the perinatal optic nerve die soon after they are formed.

    “It has been estimated that ∼50% of OLs in the perinatal optic nerve die soon after they are formed (Barres et al., 1992).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Barres et al., 1992 source

  • May combine two claims.

    Interpretationreasoning

    In P60 corpus callosum, TC is approximately 9.5 days, implying that a number of new cells equal to the starting population must be formed within 9.5 days.

    “For example, in the P60 corpus callosum, the OP cell-cycle time (TC) is ∼9.5 days (Table 1), implying that a number of new cells equal to the starting population must be formed within 9.5 days (because all OPs are dividing).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The previous estimate of GF≈50% was too low, possibly reflecting suboptimal antigen retrieval or inhibition of cell division by BrdU.

    “We now accept that our previous estimate of GF≈50% was too low, possibly reflecting suboptimal antigen retrieval or inhibition of cell division by BrdU (see Figure S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pdgf-AA is released from neuronal cell bodies in the retina but not from their axons in the optic nerve.

    “Against this idea, we showed previously that an important neuron-derived OP mitogen, platelet-derived growth factor (A-chain homodimers, Pdgf-AA), is released from neuronal cell bodies in the retina but not from their axons in the optic nerve (Fruttiger et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fruttiger et al., 2000 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The local density of unmyelinated axons might be one factor that influences local proliferation rates.

    “The fact that there are many more unmyelinated axons in the adult corpus callosum (TC ≈10 days) than in the optic nerve (TC ≈20 days) suggests that the local density of unmyelinated axons might be one factor that influences local proliferation rates, perhaps because mitogens are released from or associated with the surfaces of unmyelinated axons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    ∼4% of newly formed OLs should also be mGFP+ because on average one new OL and one replacement OP is formed for every OP division.

    “so ∼4% of newly formed OLs should also be mGFP+ (because on average one new OL and one replacement OP is formed for every OP division)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: On average one new OL and one replacement OP is formed for every OP division.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    EdU at 0.2 mg/ml in drinking water was determined to be nontoxic.

    “EdU (Invitrogen) was dissolved in the drinking water at 0.2 mg/ml, which we had determined to be nontoxic (Figures S1 and S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    There are many more adult-born OLs than would be required to myelinate the approximately 1% of axons that remain unmyelinated at that age, given that late-generated OLs synthesize as much or more myelin sheath as those born earlier.

    “However, our observations contradicted this prediction; we found that ∼6.5% of CC1+-differentiated OLs in the optic nerve were generated between P120 and P185, so there are many more adult-born OLs than would be required to myelinate the ∼1% of axons that remain unmyelinated at that age, given that late-generated OLs synthesize as much or more myelin sheath as those born earlier (see next parag”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Butt et al. (1994) measured randomly selected, dye-injected OLs in optic nerves from mice aged between P30 and P60, and counted ∼19 internodes per cell with an average length ∼138 μm.

    “Butt et al. (1994) measured randomly selected, dye-injected OLs in optic nerves from mice aged between P30 and P60, and counted ∼19 internodes per cell with an average length ∼138 μm.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Butt et al. (1994) source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Internode length and the number of internodes elaborated per OL vary greatly between CNS regions.

    “Internode length and the number of internodes elaborated per OL vary greatly between CNS regions (Butt et al., 1994; Murtie et al., 2007; Chong et al., 2012)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Butt et al., 1994 source
    • cites Murtie et al., 2007 source
    • cites Chong et al., 2012 source

  • May combine two claims.

    Interpretationown data

    If new internodes are laid down in pairs, then each one of the pair must come from a separate OL.

    “if new internodes are laid down in pairs, then each one of the pair must come from a separate OL.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    We calculated the required correction for sampling error due to section thickness to be 3πT/(3πT-4r) ≈1.42 for P30+30, 1.50 for P50+30/65, and 1.64 for P120+65.

    “We calculated the required correction (for r < T < 2r) to be 3πT/(3πT-4r) ≈1.42 for P30+30, 1.50 for P50+30/65, and 1.64 for P120+65 (Figure S4).”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    The fraction of OPs labeled by tamoxifen induction (approximately 20%) is representative of all OPs, so the proportion of all CC1+ cells born after P120 can be estimated by dividing the YFP+ CC1+ fraction by 0.20.

    “Because only ∼20% of OPs were YFP-labeled by tamoxifen induction, this implies that 6.5% ± 1.5% [(1.3 ± 0.3) × 100/20] of all CC1+ cells in the P185 optic nerve are born after P120.”

  • The authors state this as an assumption.

    The cell-cycle time continues to increase linearly with age after P60 at the same rate that it increases between P21 and P60.

    “assuming that the cell-cycle time continues to increase linearly with age after P60 at the same rate that it increases between P21 and P60 (Table 1)”

  • The authors state this as an assumption.

    All additional cells produced by OP divisions would differentiate into OLs and survive.

    “If all of these additional cells were to differentiate into OLs and survive”

  • The authors state this as an assumption.

    mGFP+ and GFP-negative OLs are equally likely to survive.

    “assuming that mGFP+ and GFP-negative OLs are equally likely to survive”

  • The paper relies on this without support.

    On average one new OL and one replacement OP is formed for every OP division.

    “because on average one new OL and one replacement OP is formed for every OP division”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The Cre/lox system has been used in reporter mice to track oligodendrogenesis and myelin synthesis during development, after CNS demyelination, and after SCI.

    “The Cre/lox system been used in reporter mice to track oligodendrogenesis and myelin synthesis during development [45, 81], after CNS demyelination [82, 83], and after SCI [44, 84, 85].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [45]

    The Experimental Procedures ('Transgenic Mice and Cre Recombination'; page unavailable) describe crossing Pdgfra-CreERT2 mice with Cre-sensitive reporters. The Results ('Late-Born OLs Generate Many More, Shorter Internodes Than Early-Born OLs'; page unavailable) use those mice to track oligodendrocytes and myelin internodes from P30 onward. This supports the reporter-mouse method, but the paper chiefly studies postnatal and adult myelination rather than establishing its use during early development—the portion of the sentence to which this source appears attached. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Myelin maintenance in white matter is actively regulated by the continuous proliferation and maturation of oligodendrocytes derived from progenitor cells throughout adulthood.

    “Myelin maintenance in white matter is actively regulated by the continuous proliferation and maturation of oligodendrocytes derived from progenitor cells throughout adulthood. 24 , 25”

    From Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes (2025) · cites this paper as [24]

    The Introduction (page not provided) reports that oligodendrocyte precursors continue dividing into adulthood and that some newly formed oligodendrocytes form myelin. The Discussion (page not provided) presents maintenance of existing myelin as a possibility, not an established function of this process throughout white matter; it also considers myelination of previously unmyelinated axons. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • OPC cell division turnover in the juvenile cortex is 19 days.

    “consistent with a cell division turnover of 19 days in the juvenile cortex (7).”

    From Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system (2016) · cites this paper as [7]

  • EdU at the dose used (0.2 mg/ml in drinking water) is nontoxic.

    “EdU at this dose is nontoxic [45].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [45]

Cites

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1 of the 56 references couldn’t be matched to a known paper.

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Related

Authors
Young, K. M., Psachoulia, K., Tripathi, R. B., Dunn, S.-J., Cossell, L., Attwell, D., Tohyama, K., & Richardson, W. D.
Affiliations
  • University of Tasmania (AU)
  • University College London (GB)
  • Microsoft Research (United Kingdom) (GB)
  • Iwate Medical University (JP)
Corresponding author
Richardson, William D.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2013-03
Volume
77
Issue
5
Pages
873-885
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2013.01.006
PMC
PMC3842597
OpenAlex
W2065770359
Cited by
872
References
56
Citations by year
2026: 43 · 2025: 55 · 2024: 51 · 2023: 50 · 2022: 60 · 2021: 92 · 2020: 64 · 2019: 81 · 2018: 74 · 2017: 91 · 2016: 66 · 2015: 62 · 2014: 56 · 2013: 26
FWCI
23.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • eCite Digital Repository (University of Tasmania) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Health and Medical Research Council
  • Medical Research Council
  • Ministry of Education, Culture, Sports, Science and Technology
  • Bupa Foundation
  • Alzheimer’s Society
  • National Institutes of Health
  • Wellcome Trust
  • Multiple Sclerosis Research Australia
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
oligodendrocyte precursor cells, myelin remodeling, adult neurogenesis, oligodendrocyte proliferation, optic nerve, internode length, myelination, axonal myelination, oligodendrocyte death, central nervous system development
MeSH terms
Aging, Animals, Cell Count, Cell Cycle, Cell Differentiation, Cell Division, Cell Survival, Central Nervous System, Immunohistochemistry, Mice, Transgenic, Myelin Sheath, Oligodendroglia, Optic Nerve, Polymerase Chain Reaction, Microscopy, Immunoelectron, Microscopy, Confocal, Receptor, Platelet-Derived Growth Factor alpha, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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