Abstract
Traumatic spinal cord injury (SCI) results in persistent functional deficits due to the lack of axon regeneration within the mammalian CNS. After SCI, chondroitin sulfate proteoglycans (CSPGs) inhibit axon regrowth via putative interactions with the LAR-family protein tyrosine phosphatases, PTPσ and LAR, localized on the injured axon tips. Unlike mammals, the sea lamprey, Petromyzon marinus, robustly recovers locomotion after complete spinal cord transection (TX). Behavioral recovery is accompanied by heterogeneous yet predictable anatomical regeneration of the lamprey’s reticulospinal (RS) system. The identified RS neurons can be categorized as “good” or “bad” regenerators based on the likelihood that their axons will regenerate. Those neurons that fail to regenerate their axons undergo a delayed form of caspase-mediated cell death. Previously, this lab reported that lamprey PTPσ mRNA is selectively expressed in “bad regenerator” RS neurons, preceding SCI-induced caspase activation. Consequently, we hypothesized that PTPσ deletion would reduce retrograde cell death and promote axon regeneration. Using antisense morpholino oligomers (MOs), we knocked down PTPσ expression after TX and assessed the effects on axon regeneration, caspase activation, intracellular signaling, and behavioral recovery. Unexpectedly, PTPσ knockdown significantly impaired RS axon regeneration at 10 weeks post-TX, primarily due to reduced long-term neuron survival. Interestingly, cell loss was not preceded by an increase in caspase or p53 activation. Behavioral recovery was largely unaffected, although PTPσ knockdowns showed mild deficits in the recovery of swimming distance and latency to immobility during open field swim assays. Although the mechanism underlying the cell death following TX and PTPσ knockdown remains unknown, this study suggests that PTPσ is not a net negative regulator of long tract axon regeneration in lampreys.
Highlights
Spinal cord injury (SCI) results in persistent functional deficits in mammals because injured CNS axons fail to regenerate
morpholino oligomers (MOs) targeting lamprey PTPσ (MO) were designed to interact with intron-exon junctions flanking an exon encoding a region in the 3rd Ig-like domain towards the N-terminal
Previous studies demonstrated that MOs applied to the cut ends of lamprey RS axons immediately after TX reach their perikarya in the brain within 1 week of injury and are effective in reducing protein expression of their target RNAs (Zhang et al, 2015; Hu et al, 2017)
Summary
Spinal cord injury (SCI) results in persistent functional deficits in mammals because injured CNS axons fail to regenerate This failure results from both inhibitory factors in the extracellular environment and intrinsic limitations to regenerative capacity (Tran et al, 2018). Starting from the extracellular N-terminal, they contain three Ig-like domains, the first of which interacts with CSPGs via conserved lysine residues These domains are followed by a number of fibronectin type III (FNIII) repeats, which vary depending on splicing. Genetic deletion or peptide inhibition of LAR and PTPσ has been reported to enhance CNS axon regeneration after SCI, likely via RhoA-dependent mechanisms (Shen et al, 2009; Fisher et al, 2011; Lang et al, 2015; Ohtake et al, 2016). In mammalian studies, targeting LAR or PTPσ in isolation was sufficient to elicit pro-regenerative functional effects, but inhibiting both receptors simultaneously additively enhanced axon outgrowth in vitro (Ohtake et al, 2016)
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