Disease relevance of Wld

• Genetic influences on cellular reactions to brain injury: activation of microglia in denervated neuropil in mice carrying a mutation (Wld(S)) that causes delayed Wallerian degeneration [1].
• The information on the position of the Wld locus should be valuable in further characterization of this gene involved in nerve degeneration and regeneration [2].
• Thus, these results clearly demonstrate that the Wld gene confers substantial neuroprotection after cerebral ischemia, and suggest a new role to that previously described for Wld(s) [3].
• In the caudate nucleus, Wld expression significantly reduced the percentage of ischemic neuronal damage after global ischemia (Wld(s), 27.7 +/- 16.8%; wild-type mice, 58.7 +/- 32.3%; P = 0.036) [3].
• We examined the response to axon injury in the facial motoneurons and dorsal root ganglion (DRG) neurons of C57BL/Ola (Wld) mice, compared with the responses of C57BL/6J mice [4].

Psychiatry related information on Wld

• In a mouse model of Huntington's disease, resveratrol-induced SIRT1 was found to protect neurons against ployQ toxicity and in Wallerian degeneration slow mice, resveratrol was found to protect the degeneration of neurons from axotomy, suggesting that resveratrol may possess therapeutic value to neuronal degeneration [5].

High impact information on Wld

• Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene [6].
• However, in the Wallerian degeneration model of nerve injury, the mitotic response of Schwann cells is completely inhibited [7].
• The levels of NGF and NGF receptor mRNA, the degree of macrophage recruitment, and the ability of sensory and motor axons to regenerate were measured in C57BL/Ola mice, in which Wallerian degeneration following a nerve lesion is very slow [8].
• Our findings highlight the fact that fibroblasts, by producing GM-CSF and thereby affecting macrophage and Schwann function, play a significant role in the cascade of molecular events and cellular interactions of Wallerian degeneration [9].
• Peripheral nerve injury is followed by Wallerian degeneration which is characterized by cellular and molecular events that turn the degenerating nerve into a tissue that supports nerve regeneration [9].

Chemical compound and disease context of Wld

• We sought more direct evidence that macrophages contribute to hyperalgesia and Wallerian degeneration by depleting macrophages with liposomes loaded with dichloromethylene diphosphonate (clodronate, Cl(2)MDP) [10].

Biological context of Wld

• This expression pattern, together with the previously established role of ubiquitination in axon degeneration, makes the chimeric gene a promising candidate for Wld [11].
• Exons of three genes were identified within the 85-kilobase tandem triplication unit of the slow Wallerian degeneration mutant mouse, C57BL/Wld(S) [11].
• The slow Wallerian degeneration mouse (C57BL/Wld(s)) is a mutant strain of mouse, with the unique phenotype of prolonged survival of the distal axon following axotomy [12].
• While searching for the slow Wallerian degeneration mutation (WldS) on distal mouse Chromosome (Chr) 4, we have identified a member of the kinesin superfamily whose predicted gene product has the N-terminal motor domain of Kif1b and a novel C-terminal cargo-binding domain homologous to Kif1a [13].
• To gain insights into the relationship between Wallerian degeneration, lesion induced tenascin-C upregulation and regrowth of axons we have investigated C57BL/Wlds (C57BL/Ola) mice, a mutant in which Wallerian degeneration is considerably delayed [14].

Anatomical context of Wld

• The C57BL/Wld s mouse is a mutant strain of mouse that shows greatly slowed Wallerian degeneration both in the central and peripheral nervous system [15].
• Ultrastructural correlates of synapse withdrawal at axotomized neuromuscular junctions in mutant and transgenic mice expressing the Wld gene [16].
• Previous studies have suggested that axotomy in juvenile (< 2 months) Wld mice induced a progressive nerve terminal withdrawal from motor endplates [16].
• However, motor nerve terminal ultrastructure was measurably different following axotomy in Wld transgenic 4836 line mice, which strongly express Wld protein: axotomized presynaptic terminals were retained, but many were significantly depleted of synaptic vesicles [16].
• These observations indicate a tight relationship between Wallerian degeneration, upregulation of tenascin-C expression and regrowth of axons, suggesting an involvement of tenascin-C in peripheral nerve regeneration [14].

Associations of Wld with chemical compounds

• These data reveal both a candidate gene for Wld and the potential of the Wld(S) mutant for studies of ubiquitin and retinoid metabolism [11].
• High resolution 1H MRS indicated that at 1 month of age, Wld brains have cytosolic levels of glutamate and phosphocholine that are significantly decreased, relative to total N-acetyl aspartate content [17].
• We found significantly decreased phosphocreatine and phosphomonoester concentrations in the brains of Wld mice at 1- and 2-months of age compared to both 6J and BALB/c mice, but we failed to find differences in the adenylate (ATP, ADP, or AMP) or phospholipid concentrations [17].
• We have studied the effect that adrenalectomy and dexamethasone treatment have on the proliferation and activation of microglia during Wallerian degeneration of the optic nerve in BALB/c mice [18].
• The first part of this study is a description of the effect of the intraneural injection of lysophosphatidyl choline into the sciatic nerves of C57BL/Wld mice [19].

Physical interactions of Wld

• Granulocyte macrophage colony stimulating factor (GM-CSF) activity is regulated by a GM-CSF binding molecule in Wallerian degeneration following injury to peripheral nerve axons [20].

Regulatory relationships of Wld

• The Wld s mice express both the normal and chimeric forms of ubiquitination factor E4 (Ube 4b) and nicotinamide mononucleotide adenylyltransferase-1 (Nmnat-1) [15].
• Myelin basic protein (MBP) processed by macrophages was reported to promote Schwann cell division during Wallerian degeneration [21].
• The role of TNF-alpha in the course of Wallerian degeneration of the sciatic nerve was studied in control and TNF-alpha deficient mice [22].
• On the basis of these data, we hypothesize that the Wallerian degeneration of white matter axons that follows SCI removes axonal support and induces apoptotic death in oligodendrocytes by triggering Bax expression [23].

Other interactions of Wld

• Therefore, axon protection in Wld s mice does not appear to be controlled by expression of Wld s protein in the axons per se and also is unlikely to be related to the different activity of Ube4b either in general ubiquitination or toward this particular substrate [15].
• There is, however, no evidence that Kif1b is the Wld gene [13].
• Tenascin-C expression during wallerian degeneration in C57BL/Wlds mice: possible implications for axonal regeneration [14].
• JE expression was also examined in C57BL/Wld(s) mice, which have delayed Wallerian degeneration associated with a failure of macrophage recruitment, and their parental C57BL/6J strain [24].
• Normal rate of Schwann cell proliferation in the MBP-deficient shiverer mouse during Wallerian degeneration [21].

Analytical, diagnostic and therapeutic context of Wld

• However, it is undetectable on Northern blots of Wld(S) brain and seems unlikely to be the Wld gene [11].
• Using immunohistochemistry, immunofluorescence and Western blotting, we have investigated the distribution of the chimeric Wld s protein and its different components in neurons of the CNS of Wld s mice and wild-type C57BL/6J mice [15].
• Western blot analysis showed that CNTF immunoreactivity in Wld nerves remained almost normal even 10 days after ligation when it was almost undetectable in control mice [25].
• Wallerian degeneration of the transected nerve could be delayed either by intraperitoneal injections of hydroxamate (Ro 31-9790), a nonspecific MMP inhibitor, or by local application of an MMP-9-specific antibody [26].
• In an effort to confirm this observation, we studied the course of Wallerian degeneration in C57BL/Ola mice aged 1 through 16 months by using quantitative morphometry, immunohistochemistry, and immunoblotting, but found the period of axonal survival after nerve transection to be no different in old versus young C57BL/Ola mice [27].

References