Axonal modulation of myelin gene expression in the peripheral nerve

LeBlanc, Andréa C.; Poduslo, Joseph F.

doi:10.1002/jnr.490260308

Cited by 112 publications

(89 citation statements)

References 56 publications

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“…P 0 levels decreased steadily following injury and reached very low levels by 10 d after injury (Fig. S1B), a rate similar to that observed in previous studies (10). The rate of myelin clearance, as indicated by loss of P 0 protein, correlated with the accumulation of Ig in the degenerating nerve.…”

Section: Resultssupporting

confidence: 87%

Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury

Vargas¹,

Watanabe²,

Singh³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

129

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Degenerating myelin inhibits axon regeneration and is rapidly cleared after peripheral (PNS) but not central nervous system (CNS) injury. To better understand mechanisms underlying rapid PNS myelin clearance, we tested the potential role of the humoral immune system. Here, we show that endogenous antibodies are required for rapid and robust PNS myelin clearance and axon regeneration. B-cell knockout JHD mice display a significant delay in macrophage influx, myelin clearance, and axon regeneration. Rapid clearance of myelin debris is restored in mutant JHD mice by passive transfer of antibodies from naïve WT mice or by an anti-PNS myelin antibody, but not by delivery of nonneural antibodies. We demonstrate that degenerating nerve tissue is targeted by preexisting endogenous antibodies that control myelin clearance by promoting macrophage entrance and phagocytic activity. These results demonstrate a role for immunoglobulin (Ig) in clearing damaged self during healing and suggest that the immune-privileged status of the CNS may contribute to failure of CNS myelin clearance and axon regeneration after injury.humoral immunity | nerve regeneration D uring the process of wound healing, rapid and efficient clearance of cellular debris is necessary for tissue regeneration (1). Myelin debris remains in white matter tracks years after an injury to the CNS in humans and primates (2, 3). The prolonged presence of myelin-associated inhibitors of axon regeneration is thought to contribute to the lack of recovery following CNS injury. Although peripheral myelin also contains inhibitors of axon regeneration, PNS myelin is rapidly cleared after injury, thereby permitting rapid axon regeneration (4-6). It is not known why the rates of clearance of PNS and CNS are so different (7).Antibodies, like other opsonins, coat exogenous debris and pathogens, thereby targeting them for clearance by phagocytes. The recognition of self antigens by natural antibodies produced by B1 cells is well documented (8). Although it is hypothesized that these antibodies may have a physiological role other than immune defense, their role in clearing necrotic cellular debris is not known (8). Therefore, we tested whether endogenous antibodies contribute to rapid removal of degenerating myelin after PNS injury, thereby promoting axon regeneration. ResultsAntibodies Accumulate in Sciatic Nerve After Injury. To investigate whether endogenous antibodies aid in removal of myelin debris, we first examined whether antibodies accumulate in peripheral nerves following injury. We compared nerve injury responses between WT and JHD mice, which have a targeted deletion of the JH locus that prevents VDJ recombination and the formation of mature B-cells and antibodies (9). Control and crushed sciatic nerves were obtained from WT and JHD mice and stained with anti-mouse Ig antibodies. Six days after crush injury, we observed a strong increase in immunoreactivity for Ig on degenerating myelin sheathes distal to the site of injury in WT but not in JHD nerves (Fig. S1A). To ...

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Section: Resultssupporting

confidence: 87%

Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury

Vargas¹,

Watanabe²,

Singh³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

129

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“…At this time-point, animals display reduced pain behavior (see Fig. 4), and MBP levels in wild-type injured sciatic nerve are normalized after initial demyelination (Gupta et al, 1988;LeBlanc and Poduslo, 1990); we confirmed the latter observation (not shown). MMP-9 gene deletion caused almost a 2-fold increase in unprocessed MBP (52 kDa) relative to wild-type ( Fig.…”

Section: Mmp-9 Controls Myelin Protein Content After Nerve Injurysupporting

confidence: 84%

“…It is known to control the breakdown of MBP (Chandler et al, 1995), a late component of myelin formation that is produced by Schwann cells in injured peripheral nerve (Gupta et al, 1988;LeBlanc and Poduslo, 1990). While MMP-9-dependent degradation of MBP has been shown in models of multiple sclerosis (Gijbels et al, 1993;Proost et al, 1993) and cerebral ischemia (Asahi et al, 2001;Cho et al, 2006), this is the first demonstration of this relationship in the PNS.…”

Section: Discussionmentioning

confidence: 94%

“…While MBP constitutes only 10-20% of PNS myelin (Jacobs, 2005), it is critical to maintaining integrity and compactness of peripheral nerve in development (Martini and Schachner, 1997) and after injury (LeBlanc and Poduslo, 1990). The importance of MMP-9 in peripheral nerve demyelination has been documented (Redford et al, 1995(Redford et al, , 1997Kieseier et al, 1999a,b;Siebert et al, 2001), but the mechanism of its action has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

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Cytokine regulation of MMP-9 in peripheral glia: Implications for pathological processes and pain in injured nerve

Chattopadhyay

Myers

Janes

et al. 2007

Brain, Behavior, and Immunity

122

113

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Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is induced in Schwann cells hours after peripheral nerve injury and controls axonal degeneration and macrophage recruitment to the lesion. Here, we report a robust (90-fold) increase in MMP-9 mRNA within 24 h after rat sciatic nerve crush (1 to 60 days time-course). Using direct injection into a normal sciatic nerve, we identify the proinflammatory cytokines TNF-α and IL-1β as potent regulators of MMP-9 expression (Taqman qPCR, zymography). Myelinating Schwann cells produced MMP-9 in response to cytokine injection and crush nerve injury. MMP-9 gene deletion reduced unstimulated neuropathic nociceptive behavior after one week post-crush and preserved myelin thickness by protecting myelin basic protein (MBP) from degradation, tested by Western blot and immunofluorescence. These data suggest that MMP-9 expression in peripheral nerve is controlled by key proinflammatory cytokine pathways, and that its removal protects nerve fibers from demyelination and reduces neuropathic pain after injury.

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“…After axon transection, denervated Schwann cells in the distal nerve segment abruptly downregulate numerous myelinrelated genes such as MBP (LeBlanc and Poduslo, 1990). These are reexpressed only when contact with in-growing axons is reestablished.…”

Section: Subfragments Of Mod4 Confer Responsiveness To Axonal Signalingmentioning

confidence: 99%

Functional Organization of a Schwann Cell Enhancer

Denarier

Forghani²,

Farhadi³

et al. 2005

J. Neurosci.

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Myelin basic protein (MBP) gene expression is conferred in oligodendrocytes and Schwann cells by different upstream enhancers. InSchwann cells, expression is controlled by a 422 bp enhancer lying Ϫ9 kb from the gene. We show here that it contains 22 mammalian conserved motifs Ն6 bp. To investigate their functional significance, different combinations of wild-type or mutated motifs were introduced into reporter constructs that were inserted in single copy at a common hypoxanthine phosphoribosyltransferase docking site in embryonic stem cells. Lines of transgenic mice were derived, and the subsequent qualitative and quantitative expression phenotypes were compared at different stages of maturation. In the enhancer core, seven contiguous motifs cooperate to confer Schwann cell specificity while different combinations of flanking motifs engage, at different stages of Schwann cell maturation, to modulate expression level. Mutation of a Krox-20 binding site reduces the level of reporter expression, whereas mutation of a potential Sox element silences reporter expression. This potential Sox motif was also found conserved in other Schwann cell enhancers, suggesting that it contributes widely to regulatory function. These results demonstrate a close relationship between phylogenetic footprints and regulatory function and suggest a general model of enhancer organization. Finally, this investigation demonstrates that in vivo functional analysis, supported by controlled transgenesis, can be a robust complement to molecular and bioinformatics approaches to regulatory mechanisms.

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Axonal modulation of myelin gene expression in the peripheral nerve

Cited by 112 publications

References 56 publications

Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury

Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury

Cytokine regulation of MMP-9 in peripheral glia: Implications for pathological processes and pain in injured nerve

Functional Organization of a Schwann Cell Enhancer

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