GAP‐43 overexpression in adult mouse Purkinje cells overrides myelin‐derived inhibition of neurite growth

Abstract

Up-regulation of growth-associated proteins in adult neurons promotes axon regeneration and neuritic elongation onto nonpermissive substrates. To investigate the interaction between these molecules and myelin-related inhibitory factors, we examined transgenic mice in which overexpression of the growth-associated protein GAP-43 is driven by the Purkinje cell-specific promoter L7. Contrary to their wild-type counterparts, which have extremely poor regenerative capabilities, axotomized transgenic Purkinje cells exhibit profuse sprouting along the intracortical neurite and at the severed stump [Buffo et al. (1997) J. Neurosci., 17, 8778-8791]. Here, we investigated the relationship between such sprouting axons and oligodendroglia to ask whether GAP-43 overexpression enables Purkinje neurites to overcome myelin-derived inhibition. Intact transgenic Purkinje axons display normal morphology and myelination. Following injury, however, many GAP-43-overexpressing neurite stumps are devoid of myelin cover and sprout into white matter regions containing densely packed myelin and Nogo-A- or MAG-immunopositive oligodendrocytes. The intracortical segments of these neurites show focal accumulations of GAP-43, which are associated with disrupted or retracted myelin sheaths. Numerous sprouts originate from such demyelinated segments and spread into the granular layer. Some myelin loss, though not axon sprouting, is also evident in wild-type mice, but this phenomenon is definitely more rapid and extensive in transgenic cerebella. Thus, GAP-43-overexpressing Purkinje axons are endowed with enhanced capabilities for growing into nonpermissive territories and show a pronounced tendency to lose myelin. Our observations suggest that accumulation of GAP-43 along precise axon segments disrupts the normal axon-glia interaction and enhances the retraction of oligodendrocytic processes to facilitate the outgrowth of neuritic sprouts.

Degradation of Chondroitin Sulfate Proteoglycans Induces Sprouting of Intact Purkinje Axons in the Cerebellum of the Adult Rat

“…In both experimental groups, there were no clear differences from previous descriptions about myelination of Purkinje axons (Gianola et al, 2003;Gianola and Rossi, 2004;Clark et al, 2005). In control material (Fig.…”

“…Injection of anti-Nogo-A antibodies in the cerebellar cortex induces sprouting from Purkinje axons in the granular layer (Buffo et al, 2000), and a similar phenomenon is observed after injury in GAP-43 (growthassociated protein-43)-overexpressing Purkinje cells (Buffo et al, 1997;Gianola and Rossi, 2004). In both conditions, in addition to the outgrowth of terminal fibers from the infraganglionic plexus, sprouting also occurs along the corticofugal neurite, and this phenomenon may be accompanied by disruption of the normal axon-myelin relationship (Gianola and Rossi, 2004).…”

“…In both conditions, in addition to the outgrowth of terminal fibers from the infraganglionic plexus, sprouting also occurs along the corticofugal neurite, and this phenomenon may be accompanied by disruption of the normal axon-myelin relationship (Gianola and Rossi, 2004).…”

A p53-CBP/p300 transcription module is required for GAP-43 expression, axon outgrowth, and regeneration

“…[7][8][9][10][11] GAP-43 contributes to axon sprouting and regeneration in the peripheral nervous system, in the optic nerve, in the Purkinje cells of the cerebellum, in mossy fibers of the hippocampus and in the raphe-spinal descending spinal tracts. [12][13][14][15] However, GAP-43 alone does not significantly promote axon regeneration of the corticospinal tracts and the dorsal root ganglia ascending spinal fibers, but does so after dorsal column lesions when overexpressed together with CAP-23. 16 Thus far, it has been shown that GAP-43 is regulated at both the transcriptional and post-transcriptional levels.…”

Intrinsic Factors Contributing to Axon Regeneration in the Mammalian Nervous System

“…Overexpression of major growth cone proteins, such as GAP-43 or CAP-23, in transgenic mice induces spontaneous sprouting in different populations of PNS and CNS neurons, and promotes collateral reinnervation at the neuromuscular junction (Aigner et al, 1995;Caroni et al, 1997). When the GAP-43 gene is specifically targeted to Purkinje cells, which are peculiar for their poor regenerative potential (Rossi et al, 1995;Dusart et al, 1997;Carulli et al, 2004), injured axons vigorously sprout into the growthinhibitory white matter environment (Buffo et al, 1997;Gianola and Rossi, 2004). Sprouting, but not regeneration, has been also reported for GAP-43 overexpressing thalamic neurons (Mason et al, 2000), indicating that up-regulation of individual genes may enhance axon plasticity, but it is not sufficient to sustain long-distance neuritic elongation.…”