Abstract
Adult mammalian central nervous system (CNS) neurons are unable to regenerate following axonal injury, leading to permanent functional impairments. Yet, the reasons underlying this regeneration failure are not fully understood. Here, we studied the transcriptome and translatome shortly after spinal cord injury. Profiling of the total and ribosome-bound RNA in injured and naïve spinal cords identified a substantial post-transcriptional regulation of gene expression. In particular, transcripts associated with nervous system development were down-regulated in the total RNA fraction while remaining stably loaded onto ribosomes. Interestingly, motif association analysis of post-transcriptionally regulated transcripts identified the cytoplasmic polyadenylation element (CPE) as enriched in a subset of these transcripts that was more resistant to injury-induced reduction at the transcriptome level. Modulation of these transcripts by overexpression of the CPE binding protein, Cpeb1, in mouse and Drosophila CNS neurons promoted axonal regeneration following injury. Our study uncovered a global evolutionarily conserved post-transcriptional mechanism enhancing regeneration of injured CNS axons.
Highlights
Axons of the adult mammalian central nervous system (CNS) have a very limited regenerative capacity following injury
We investigated whether there is a link between AUrich elements (AREs) and cytoplasmic polyadenylation element (CPE), Pumilio binding element (PBE), Musashi binding element (MBE), and Hex, and found that they tend to co-occur in the mouse transcriptome
A screening of factors showing this uncoupled behavior in Drosophila sLNvs revealed that 50% of the transcripts being prioritized for translation despite exhibiting reduced levels following spinal injury modulated axonal growth of developing neurons in the fly
Summary
Axons of the adult mammalian CNS have a very limited regenerative capacity following injury. Cpeb Regulates CNS Axonal Regeneration the lesion, a level of functionality could potentially be recovered by rewiring the circuit. Besides the weak and sterile end of axotomized axons set to degenerate, there are active axonal ends, capable of sprouting, for which he termed “bud” or “club of growth”, due to their analogy to the growth cones of embryonic axons This initial attempt to regrow is largely unsuccessful and eventually stops (Cajal et al, 1991). Successful regrowth of central DRG axons as induced by a preconditioning peripheral lesion requires the assembly of these regenerating terminal bulbs that are observed 5–7 h following injury (Ylera et al, 2009). As a result, studying the early post-injury phase could reveal key information, from which we could learn how neurons behave in a regeneration-permissive state, and more importantly, whether this state could be extended to promote axonal regeneration
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