Differential effects of autologous peripheral nerve grafts to the corpus striatum of adult rats on the regeneration of axons of striatal and nigral neurons and on the expression of GAP-43 and the cell adhesion molecules N-CAM and L1

Abstract

A segment of tibial nerve was autografted to the right corpus striatum of deeply anesthetized adult rats; the distal graft was left beneath the scalp. Horseradish peroxidase (HRP) conjugates were injected into the distal graft after 2-30 weeks, and the animals were killed 2-3 days later. Small numbers of neostriatal perikarya were HRP labeled at all survival times; most were large (ca. 20 microm in diameter), and many contained acetycholine esterase (AChE). Many more neurons were labelled in the substantia nigra pars compacta (SNpc) 4 weeks or more after grafting. When the graft encroached on the globus pallidus, numerous pallidal neurons, most of them AChE positive, were also labeled. Nigrostriatal neurons, a population of pallidal cholinergic neurons, and a subclass (or classes) of neostriatal neurons, including cholinergic interneurons, thus can be classified as central nervous system (CNS) neurons with a relatively strong regenerative response. In a second experimental series, animals were killed 1-4 weeks after grafting, and sections were probed for the expression of mRNAs encoding growth-associated protein 43 (GAP-43) and the cell adhesion molecules N-CAM and L1. Subpopulations of mostly large neurons scattered throughout the neostriatum gave moderate signals for GAP-43 and N-CAM mRNAs and a stronger signal for L1 mRNAs. Most SNpc neurons were strongly labeled with all three probes. Neostriatal grafts had no apparent effect on the expression of any of the mRNAs in the SNpc or on L1 and N-CAM mRNAs in the striatum. However, GAP-43 mRNA levels were increased in a few, mainly large neostriatal neurons around the graft tip, resembling the HRP-labeled cells. In contrast, previous work has shown upregulation (from an undetectable level) of GAP-43 and L1 mRNAs in neurons regenerating axons into grafts placed in the thalamus and cerebellum. Thus, GAP-43 and L1 mRNA expression, but not necessarily marked upregulation, may correlate with, and be intrinsic determinants of, the ability of CNS neurons to regenerate their axons.

Delayed Applications of L1 and Chondroitinase ABC Promote Recovery after Spinal Cord Injury

“…Abundant evidence has accumulated showing that L1 expression levels and axon regeneration in the CNS are correlated. Retinal ganglion cells, nigrostriatal and cholinergic neostriatal neurons express relatively high levels of L1, and are able to regenerate axons along a peripheral nerve graft without upregulation of L1 expression (Becker et al, 2001;Jung et al, 1997;Woolhead et al, 1998). Neurons in the thalamic reticular nucleus express low levels of L1 and CHL1, but are capable of upregulating these proteins, and also successfully regrow into the graft (Chaisuksunt et al, 2000a;Zhang et al, 1995).…”

Unexpected Kif4a functions in adult regeneration encompass a dual role in neurons and in proliferative repair Schwann cells

“…Further, under conditions in which regeneration of a severed rat sciatic nerve was enhanced by implantation of a conduit 68 , KIF4A was highly abundant in axonal tracts also stained for GAP-43 (Figure 7B-C). This established RAG is strongly up-regulated during neuronal regeneration and correlates with enhanced regenerative capacity 26,42 .…”

“…Importantly, exogenous KIF4A transfection resulted in apoptosis of cultured cortical neurons instead of increasing b1-integrin transport 38 , highlighting the crucial need to tightly control KIF4A levels. Another important KIF4A cargo transported into the axonal growth cones is L1, which can promote neurite elongation in embryonic cultured neurons 39,41 and supports neuronal regeneration in both adult CNS and PNS 26,42 . All these facts strongly suggest a relevant function for KIF4A in neuronal intrinsic regeneration processes, although further studies are needed to investigate its precise role and mechanisms of action.…”

“…These include the ribosomal protein P0 in developing dorsal root ganglia (DRG) neurons 40 , and the L1 neuritogenic neural cell adhesion molecules (CAM) of the immunoglobulin superfamily 40,41 in hippocampal neurons 39 . Importantly, L1 protein (alias L1CAM) has already been related to regeneration of both adult central and peripheral neurons 26,42,43 . KIF4A also binds to and anterogradely transports other neuronal CAMs, like TAX1 39 and b1-integrin, in immature neurons 38 .…”