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Axonal control of oligodendrocyte development.

Barres BA, Raff MC - J. Cell Biol. (1999)

View Article: PubMed Central - PubMed

Affiliation: Stanford University School of Medicine, Department of Neurobiology, Stanford, California 94305-5125, USA. barres@stanford.edu

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The number of some glial cells that survive also appears to depend on a competition for neuron-derived survival signals... In particular, the number of myelinating glial cells that survive appears to be precisely matched during development to the number and lengths of axons requiring myelination... Oligodendrocytes are postmitotic cells that develop from oligodendrocyte precursor cells (OPCs) that migrate into developing white matter from their germinal zones... The final number of oligodendrocytes in any part of the CNS could, in principle, depend upon the number of OPCs that migrate into it, the number of times the OPCs divide before they differentiate, and the number of oligodendrocytes and OPCs that undergo normal cell death in the region... When PDGF concentration is low, most of the cells become oligodendrocytes... Therefore, the failure of axotomy to influence the percentage of OPCs that incorporate BrdU does not necessarily mean that axons do not regulate their division... How do axons regulate oligodendrocyte survival? Oligodendrocytes do not die if the optic nerve is transected in WLD mutant mice in which the axons do not degenerate (Brown et al. 1991) and the ability of axons to promote oligodendrocyte survival does not depend on electrical activity in the axons (Barres et al. 1993b)... In these experiments they transected P4 nerves rather than P0 nerves in order to allow time for at least some oligodendrocytes to be generated, and then examined the nerves at P7... They found no change in the density of surviving oligodendrocytes or the percentage of oligodendrocytes undergoing apoptosis, suggesting to them that axons do not control oligodendrocyte survival... Interpretation of these findings, however, is limited by the fact that very few oligodendrocytes are normally found in the optic nerve at P4 (Miller et al. 1985; Barres et al. 1992)... Thus nearly all of the oligodendrocytes examined between P4 and P7 would be newly formed oligodendrocytes, which do not yet depend on axons to survive (Barres et al. 1993b). (That a small percentage of these oligodendrocytes are mature enough to depend on axons is suggested by the observation of Ueda et al. 1999 that there is a substantial increase in oligodendrocyte death one day after axotomy.) Clearly, for the effects of axons on oligodendrocyte survival to be examined meaningfully, axotomy must be performed at a later postnatal age after a significant number of oligodendrocytes have been generated, as was done previously (Fulcrand and Privat 1977; Privat et al. 1981; Barres et al. 1993b)... Nonetheless, Trapp and colleagues concluded that their data “argue against axonal regulation of optic nerve oligodendrogenesis. ” In fact, whereas the new data of Trapp and colleagues provides evidence that axons do not strongly promote the survival of just born oligodendrocytes, their new studies do not address whether axons promote the survival of oligodendrocytes that are at least 2 to 3 d beyond their birthday or older, as suggested by the studies of Barres et al. 1992, Barres et al. 1994(see below)... Recent studies have revealed that axons promote oligodendrocyte development by helping to drive the proliferation of OPCs and by promoting the survival of mature, myelinating oligodendrocytes.

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A model for how oligodendrocyte number is matched to axonal surface area. Once an OPC stops dividing and differentiates into an oligodendrocyte (left side of figure), it has 2–3 d to contact an unmyelinated region of axon, which provides a new signal that the cell requires for continued survival. Astrocyte-derived signals, such as PDGF, can promote the survival of newly formed oligodendrocytes for at least 2 d (middle of figure). But as the newly formed oligodendrocytes undergo further maturation (right side of figure), they lose responsiveness to these astrocyte-derived signals and require an axonal signal to survive. Those that fail to contact an axon by 3 d after generation undergo apoptosis.
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Figure 1: A model for how oligodendrocyte number is matched to axonal surface area. Once an OPC stops dividing and differentiates into an oligodendrocyte (left side of figure), it has 2–3 d to contact an unmyelinated region of axon, which provides a new signal that the cell requires for continued survival. Astrocyte-derived signals, such as PDGF, can promote the survival of newly formed oligodendrocytes for at least 2 d (middle of figure). But as the newly formed oligodendrocytes undergo further maturation (right side of figure), they lose responsiveness to these astrocyte-derived signals and require an axonal signal to survive. Those that fail to contact an axon by 3 d after generation undergo apoptosis.

Mentions: A tentative model for how a competition for axon-dependent survival signals may help to match oligodendrocyte and axon numbers during development has been proposed (Barres et al. 1993b; Barres and Raff 1994). Once an oligodendrocyte precursor cell stops dividing and begins to differentiate into an oligodendrocyte, its specific requirements for survival signals change: it rapidly loses its PDGF receptors, for example, so that PDGF can no longer promote its survival (Hart et al. 1989; McKinnon et al. 1990). It now has only 2–3 d to contact a nonmyelinated region of axon that provides new signals that are required for its continued survival. A cell that fails to find an axon will kill itself (Fig. 1). Forcing oligodendrocytes to compete for axon-dependent survival signals that are limited in amount or availability would help to ensure that the final number of oligodendrocytes is precisely matched to the number (and length) of axons requiring myelination. Importantly, according to this model, newly formed premyelinating oligodendrocytes depend on astrocyte-derived signals for their survival for about the first 2 d, whereas after 3 d the oligodendrocytes are more mature and depend primarily upon an axon-derived signal.


Axonal control of oligodendrocyte development.

Barres BA, Raff MC - J. Cell Biol. (1999)

A model for how oligodendrocyte number is matched to axonal surface area. Once an OPC stops dividing and differentiates into an oligodendrocyte (left side of figure), it has 2–3 d to contact an unmyelinated region of axon, which provides a new signal that the cell requires for continued survival. Astrocyte-derived signals, such as PDGF, can promote the survival of newly formed oligodendrocytes for at least 2 d (middle of figure). But as the newly formed oligodendrocytes undergo further maturation (right side of figure), they lose responsiveness to these astrocyte-derived signals and require an axonal signal to survive. Those that fail to contact an axon by 3 d after generation undergo apoptosis.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2168096&req=5

Figure 1: A model for how oligodendrocyte number is matched to axonal surface area. Once an OPC stops dividing and differentiates into an oligodendrocyte (left side of figure), it has 2–3 d to contact an unmyelinated region of axon, which provides a new signal that the cell requires for continued survival. Astrocyte-derived signals, such as PDGF, can promote the survival of newly formed oligodendrocytes for at least 2 d (middle of figure). But as the newly formed oligodendrocytes undergo further maturation (right side of figure), they lose responsiveness to these astrocyte-derived signals and require an axonal signal to survive. Those that fail to contact an axon by 3 d after generation undergo apoptosis.
Mentions: A tentative model for how a competition for axon-dependent survival signals may help to match oligodendrocyte and axon numbers during development has been proposed (Barres et al. 1993b; Barres and Raff 1994). Once an oligodendrocyte precursor cell stops dividing and begins to differentiate into an oligodendrocyte, its specific requirements for survival signals change: it rapidly loses its PDGF receptors, for example, so that PDGF can no longer promote its survival (Hart et al. 1989; McKinnon et al. 1990). It now has only 2–3 d to contact a nonmyelinated region of axon that provides new signals that are required for its continued survival. A cell that fails to find an axon will kill itself (Fig. 1). Forcing oligodendrocytes to compete for axon-dependent survival signals that are limited in amount or availability would help to ensure that the final number of oligodendrocytes is precisely matched to the number (and length) of axons requiring myelination. Importantly, according to this model, newly formed premyelinating oligodendrocytes depend on astrocyte-derived signals for their survival for about the first 2 d, whereas after 3 d the oligodendrocytes are more mature and depend primarily upon an axon-derived signal.

View Article: PubMed Central - PubMed

Affiliation: Stanford University School of Medicine, Department of Neurobiology, Stanford, California 94305-5125, USA. barres@stanford.edu

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The number of some glial cells that survive also appears to depend on a competition for neuron-derived survival signals... In particular, the number of myelinating glial cells that survive appears to be precisely matched during development to the number and lengths of axons requiring myelination... Oligodendrocytes are postmitotic cells that develop from oligodendrocyte precursor cells (OPCs) that migrate into developing white matter from their germinal zones... The final number of oligodendrocytes in any part of the CNS could, in principle, depend upon the number of OPCs that migrate into it, the number of times the OPCs divide before they differentiate, and the number of oligodendrocytes and OPCs that undergo normal cell death in the region... When PDGF concentration is low, most of the cells become oligodendrocytes... Therefore, the failure of axotomy to influence the percentage of OPCs that incorporate BrdU does not necessarily mean that axons do not regulate their division... How do axons regulate oligodendrocyte survival? Oligodendrocytes do not die if the optic nerve is transected in WLD mutant mice in which the axons do not degenerate (Brown et al. 1991) and the ability of axons to promote oligodendrocyte survival does not depend on electrical activity in the axons (Barres et al. 1993b)... In these experiments they transected P4 nerves rather than P0 nerves in order to allow time for at least some oligodendrocytes to be generated, and then examined the nerves at P7... They found no change in the density of surviving oligodendrocytes or the percentage of oligodendrocytes undergoing apoptosis, suggesting to them that axons do not control oligodendrocyte survival... Interpretation of these findings, however, is limited by the fact that very few oligodendrocytes are normally found in the optic nerve at P4 (Miller et al. 1985; Barres et al. 1992)... Thus nearly all of the oligodendrocytes examined between P4 and P7 would be newly formed oligodendrocytes, which do not yet depend on axons to survive (Barres et al. 1993b). (That a small percentage of these oligodendrocytes are mature enough to depend on axons is suggested by the observation of Ueda et al. 1999 that there is a substantial increase in oligodendrocyte death one day after axotomy.) Clearly, for the effects of axons on oligodendrocyte survival to be examined meaningfully, axotomy must be performed at a later postnatal age after a significant number of oligodendrocytes have been generated, as was done previously (Fulcrand and Privat 1977; Privat et al. 1981; Barres et al. 1993b)... Nonetheless, Trapp and colleagues concluded that their data “argue against axonal regulation of optic nerve oligodendrogenesis. ” In fact, whereas the new data of Trapp and colleagues provides evidence that axons do not strongly promote the survival of just born oligodendrocytes, their new studies do not address whether axons promote the survival of oligodendrocytes that are at least 2 to 3 d beyond their birthday or older, as suggested by the studies of Barres et al. 1992, Barres et al. 1994(see below)... Recent studies have revealed that axons promote oligodendrocyte development by helping to drive the proliferation of OPCs and by promoting the survival of mature, myelinating oligodendrocytes.

Show MeSH