Abstract
The sea lamprey has been used as a model for the study of axonal regeneration after spinal cord injury. Previous studies have suggested that, unlike developing axons in mammal, the tips of regenerating axons in lamprey spinal cord are simple in shape, packed with neurofilaments (NFs), and contain very little F-actin. Thus it has been proposed that regeneration of axons in the central nervous system of mature vertebrates is not based on the canonical actin-dependent pulling mechanism of growth cones, but involves an internal protrusive force, perhaps generated by the transport or assembly of NFs in the distal axon. In order to assess this hypothesis, expression of NFs was manipulated by antisense morpholino oligonucleotides (MO). A standard, company-supplied MO was used as control. Axon retraction and regeneration were assessed at 2, 4 and 9 weeks after MOs were applied to a spinal cord transection (TX) site. Antisense MO inhibited NF180 expression compared to control MO. The effect of inhibiting NF expression on axon retraction and regeneration was studied by measuring the distance of axon tips from the TX site at 2 and 4 weeks post-TX, and counting the number of reticulospinal neurons (RNs) retrogradely labeled by fluorescently-tagged dextran injected caudal to the injury at 9 weeks post-TX. There was no statistically significant effect of MO on axon retraction at 2 weeks post-TX. However, at both 4 and 9 weeks post-TX, inhibition of NF expression inhibited axon regeneration.
Highlights
The sea lamprey is a convenient model for the study of axon regeneration after spinal cord injury (SCI), in part because identified reticulospinal neurons (RNs) with known, heterogeneous regenerative abilities can be imaged in histological whole-mounts [1, 2]
This calls into question the idea that regeneration recapitulates the mechanism of early axon development, and it has been proposed that regeneration of axons in the central nervous system (CNS) of mature vertebrates is not based on the canonical actin-dependent pulling mechanism of growth cones, but involves an internal protrusive force, perhaps generated by the transport or assembly of NFs in the distal axon [12, 13]
The net persistent reduction of NF180 mRNA expression even in good regenerators was a potential argument against this hypothesis, but we argued that because most of the axoplasm of RNs had been amputated by TX, and because NFs turn over slowly, less mRNA was needed to supply the remaining axons and to participate in their regeneration
Summary
The sea lamprey is a convenient model for the study of axon regeneration after spinal cord injury (SCI), in part because identified reticulospinal neurons (RNs) with known, heterogeneous regenerative abilities can be imaged in histological whole-mounts [1, 2]. Unlike developing axons, the tips of regenerating axons in lamprey spinal cord are simple in shape, packed with neurofilaments (NFs), and contain some microtubules but very little F-actin [11,12,13,14] This calls into question the idea that regeneration recapitulates the mechanism of early axon development, and it has been proposed that regeneration of axons in the central nervous system (CNS) of mature vertebrates is not based on the canonical actin-dependent pulling mechanism of growth cones, but involves an internal protrusive force, perhaps generated by the transport or assembly of NFs in the distal axon [12, 13]. The secondary upregulation of NF message is not a consequence of axon growth, but may be part of an intrinsic growth program executed only in neurons with a strong propensity for regeneration
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