The effects of a lesion or a peripheral nerve graft on GAP-43 upregulation in the adult rat brain: an in situ hybridization and immunocytochemical study

Abstract

We have sought to determine (1) if thalamic neurons upregulate the growth associated protein GAP-43 as a response to injury, or if a peripheral nerve graft is required to induce, enhance or sustain such a response, and (2) if thalamic neurons with different regenerative potentials also display different GAP-43 responses. Levels of GAP-43 protein (detected by LM and EM immunohistochemistry) and of GAP-43 mRNA (detected by in situ hybridization) were compared in the thalamus of adult rats between 1 d and 180 d after making a stab lesion or after implanting a peripheral nerve autograft. Stab injury is a sufficient stimulus to cause a transient upregulation in GAP-43 expression by neurons in the thalamus (both around the graft tip and in particular in the thalamic reticular nucleus) in the first week after injury but this response is both prolonged, and enhanced in the presence of a peripheral nerve graft. In addition, we demonstrate directly, by double labelling, that neurons of the thalamic reticular nucleus displaying high levels of the mRNA for GAP-43, have axons regenerating in the distal portion of the graft. These findings lend direct support to the hypothesis that upregulation of the GAP-43 gene is essential for prolonged regenerative axonal growth. We also demonstrate GAP-43 protein in graft Schwann cells and in brain astrocytes close to the site of graft implantation.

Promoting axonal regeneration in the central nervous system by enhancing the cell body response to axotomy

“…This expression correlated with the ability of injured rubrospinal neurons to regenerate into PN transplants inserted into the cervical but not the thoracic spinal cord. Similar observations have been made in other CNS neuronal systems (Vaudano et al, 1995;Anderson et al, 1998). Although it is tempting to attribute the observed axonal regeneration to the increase in GAP-43 expression, one should not overlook the fact that these proximal axotomies invariably induce a battery of other RAGs, such as L1 and c-jun (Chaisuksunt et al, 2000), plus many others that may not yet be characterized.…”

Chronic Enhancement of the Intrinsic Growth Capacity of Sensory Neurons Combined with the Degradation of Inhibitory Proteoglycans Allows Functional Regeneration of Sensory Axons through the Dorsal Root Entry Zone in the Mammalian Spinal Cord

“…Zymosan is a nontoxic but extremely potent inflammatory agent that, when placed within the vitreous chamber adjacent to the retinal ganglion cells, can drive regenerating optic fibers past a crush lesion of the optic nerve (Leon et al, 2000). Our results suggest that zymosan, when placed in the DRG, can upregulate regenerationpromoting proteins, such as GAP-43, in the central axon even in the absence of a lesion (Chong et al, 1994;Vaudano et al, 1995). Unfortunately, zymosan cannot be used in the CNS because it induces cyst formation (Fitch et al, 1999).…”

Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants

“…B-50/ GAP-43 has been related to terminal axon arbor remodeling (Caroni and Grandes, 1990;Mehta et al, 1993;Verzé et al, 1996). In addition, several adult neuron populations upregulate this protein after axotomy (Skene, 1989(Skene, , 1992Doster et al, 1991;Tetzlaff et al, 1991Tetzlaff et al, , 1994Verhaagen et al, 1993;Schaden et al, 1994), and this expression can be enhanced by growth-promoting environmental cues (Hüll and Bähr, 1994;Robinson, 1994;Vaudano et al, 1995;Chong et al, 1996). Thus, although the precise role of B-50/GAP-43 in axon growth is still debated, its expression has been strictly associated with the plastic and regenerative potential of adult neurons.…”