Evidence that Very Slow Wallerian Degeneration in C57BL/Ola Mice is an Intrinsic Property of the Peripheral Nerve

Abstract

We have described a mutant mouse, C57BL/Ola, in which Wallerian degeneration following peripheral nerve transection is very slow. Our previous results suggested that recruited monocytes play a role in rapid Wallerian degeneration. The nature of the mutation in C57BL/Ola mice is not known and we have investigated whether the defect is intrinsic to the nerve or due to a defect in the circulating monocytes. We have made chimaeric mice in which bone marrow from histocompatible mice, with rapidly degenerating nerves and normal monocyte recruitment, was used to reconstitute irradiated C57BL/Ola mice and vice-versa. A substantial degree of donor repopulation of the hosts was confirmed by measures of the levels of glucose-phosphate isomerase alloenzymes in blood and tissue samples from the two different strains. The rate of degeneration of the transected sciatic nerve was found to be host-dependent, providing evidence that the mutation affects cell populations intrinsic to the nerve and not the circulating monocytes. We provide additional evidence that the peripheral nerves of C57BL/Ola mice are different from those of other mice as they degenerate at a slower rate in vitro.

Temperature Modulation Reveals Three Distinct Stages of Wallerian Degeneration

“…On returning the nerves to 37°C after 3-4 d at 25°C, the CAP also returned to values not significantly different from those nerves incubated for the same length of time at 37°C (data not shown), similar to the effect seen in wild-type nerves. At 37°C in vitro the nerve survival was prolonged to 9 d, further extending previous data (Perry et al, 1990b;Tsao et al, 1994).…”

“…Using previously described methods (Perry et al, 1990b(Perry et al, , 1992, we analyzed the maximal peak height and peak area of both A and C waves with the Sigavg Program (C ambridge Electronic Design, C ambridge, UK) after digitization (CED 1401) at 80 kHz and found them to be equivalent (Tsao et al, 1994). Selected nerves were fixed in 2% paraformaldehyde, osmicated for 2 hr, infiltrated with glycerol, and then teased apart and examined by light microscopy.…”

TNFα-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve

“…The Wld S mouse strain displays a phenotype of slow Wallerian degeneration due to spontaneous mutation on chromosome 4 (Lyon et al, 1993) that is intrinsic to axons (Lunn et al, 1989;Perry et al, 1990) and is identified as an 85-kb tandem triplication (Coleman et al, 1998) that translates into a neuroprotective chimeric fusion protein of ubiquitin assembly factor E4B (Ube4b) and mononucleotide adenylyltransferase (Nmnat) (Conforti et al, 2000). Using the model of Wld S degeneration, we found a positive correlation between TNFα and MMP-9 expression and the macrophage migration capacity of injured nerve.…”

Elevated Neuronal Expression of CD200 Protects Wlds Mice from Inflammation-Mediated Neurodegeneration

“…9 -13 Experiments using bone marrow chimaeras have proven that this is a property that affects "cell populations intrinsic to the Wld s nerve and is not attributable to an anomaly in circulating monocytes." 14 We have recently shown that compared with wild-type (WT) mice, Wld s mice, when immunized to induce chronic EAE, developed a delayed onset and an attenuated disease course, 15 which was associated with a reduction in both axonal loss and demyelination in spinal cord sections. Axonal protection in Wld s mice was associated with increased nicotinamide adenine dinucleotide (NAD) levels; however, the molecular mechanisms mediating axon protection in Wld s mice have not been elucidated.…”