Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve

Abstract

Wallerian degeneration of the distal stump of a severed peripheral nerve involves invasion by myelomonocytic cells, whose presence is necessary for destruction of myelin and for initiating mitosis in Schwann cells (Beuche and Friede, 1984). Degeneration of the distal ends of the axons themselves is assumed to occur by autolytic mechanisms. We describe a strain of mice (C57BL/6/Ola) in which leucocyte invasion is slow and sparse. In these mice, confirming Beuche and Friede, myelin removal is extremely slow. A new finding is that axon degeneration is also very slow. This is a consequence of lack of recruitment of myelomonocytic cells for if such recruitment is prevented in other mouse strains by a monoclonal antibody against the complement type 3 receptor (Rosen and Gordon, 1987) axon degeneration is again slowed. We have also, surprisingly, found that nerve regeneration in the C57BL/6/Ola mice is not impeded by the presence of largely intact axons in the distal stump and absence of recruited cells, myelin debris and the absence of Schwann cell mitosis.

NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration

“…To put this low stringency in perspective, most axons in Wld S homozygotes survive structurally even 14 days after lesioning. 6,15,23,24 First, we studied 3-day lesioned distal nerve stumps using electron microscopy ( Figure 3 and Supplementary Figure 3). In Wld S heterozygotes, most axons displayed normal cytoskeleton, unswollen mitochondria and a regular myelin sheath of normal thickness.…”

“…6 Our groups showed that the gene identified by positional cloning [12][13][14] delays Wallerian degeneration in transgenic mice and virally transduced dorsal root ganglion (DRG) explant cultures. 15,16 Wld S encodes a fusion protein containing 70 N-terminal amino acids of ubiquitination factor Ube4b, full-length nicotinamide adenine dinucleotide (NAD þ )-synthesising enzyme nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), and a unique 18-amino-acid joining sequence.…”

WldS, Nmnats and axon degeneration-progress in the past two decades

“…An important landmark is the discovery of a spontaneous mutant mouse strain, C57BL/Wld s , whose axons survived for as long as weeks after transection (Lunn et al, 1989;Glass et al, 1993). Genetic analysis suggests that the slow Wallerian degeneration phenotype can be attributed to a dominant mutation that acts intrinsically in neurons (Perry et al, 1990;Deckwerth and Johnson, 1994;Ferri et al, 2003).…”

The role of macrophages in models of neurological and psychiatric disorder

“…Macrophages are rapidly recruited to the distal segment of an injured peripheral nerve; they phagocytose the debris and may also play a part in initiating Schwann cell division Stoll et al 1989a, b). In a remarkable mutant mouse in which peripheral nerves undergo very slow Wallerian degeneration and monocytes are not recruited (Lunn et al 1989), the absence of Wallerian degeneration and the lack of macrophage recruitment does not impede regeneration of motor fibres (Lunn et al 1989). However, sensory nerve fibres do not grow well down this undegenerated territory (Brown et al 1991).…”

“…The failure of monocyte recruitment in this mutant mouse results in a paucity of nerve growth factor production (Brown et al 1991). It appears that recruitment of monocytes is an important part of the regeneration process and may also potentiate the rate of Wallerian degeneration (Lunn et al 1989). …”