An 85-kb tandem triplication in the slow Wallerian degeneration ( Wld ^s ) mouse

Abstract

Wallerian degeneration is the degeneration of the distal stump of an injured axon. It normally occurs over a time course of around 24 hr but it is delayed in the slow Wallerian degeneration mutant mouse (C57BL͞Wld s ) for up to 3 weeks. The gene, which protects from rapid Wallerian degeneration, Wld, previously has been mapped to distal chromosome 4. This paper reports the fine genetic mapping of the Wld locus, the generation of a 1.4-Mb bacterial artificial chromosome and P1 artificial chromosome contig, and the identification of an 85-kb tandem triplication mapping within the candidate region. The mutation is unique to C57BL͞Wld s among 36 strains tested and therefore is a strong candidate for the mutation that leads to delayed Wallerian degeneration. There are very few reports of tandem triplications in a vertebrate and no evidence for a mutation mechanism so this unusual mutation was characterized in more detail. Sequence analysis of the boundaries of the repeat unit revealed a minisatellite array at the distal boundary and a matching 8-bp sequence at the proximal boundary. This finding suggests that recombination between short homologous sequences (''illegitimate'' or ''nonhomologous'' recombination) was involved in the rearrangement. In addition, a duplication allele was identified in two Wld s mice, indicating some instability in the repeat copy number and suggesting that the triplication arose from a duplication by unequal crossing over.

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.…”

Guidance Molecules in Axon Pruning and Cell Death

“…Notably, molecular mechanisms involved in axon pruning in Drosophila share similarities with Wallerian degeneration in vertebrates. Wallerian degeneration is thought to be mediated by an intrinsic mechanism of axon self-destruction (Avery et al 2009;Coleman et al 1998;Conforti et al 2000;Lunn et al 1989;Mack et al 2001), which also involves the ubiquitin-proteosome system Zhai et al 2003).…”

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

“…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.…”