Neuronal, but not glial, Contactin 2 negatively regulates axon regeneration in the injured adult optic nerve

Abstract

Mammalian adult neurons of the central nervous system (CNS) display limited ability to regrow axons after trauma. The developmental decline in their regenerative ability has been attributed to both intrinsic and extrinsic factors, including postnatal suppression of transcription factors and non-neuronal inhibitory components, respectively. The cell adhesion molecule Contactin 2 (CNTN2) is expressed in neurons and oligodendrocytes in the CNS. Neuronal CNTN2 is highly regulated during development and plays critical roles in axon growth and guidance and neuronal migration. On the other hand, CNTN2 expressed by oligodendrocytes interferes with the myelination process, with its ablation resulting in hypomyelination. In the current study, we investigate the role of CNTN2 in neuronal survival and axon regeneration after trauma, in the murine optic nerve crush (ONC) model. We unveil distinct roles for neuronal and glial CNTN2 in regenerative responses. Surprisingly, our data show a conflicting role of neuronal and glial CNTN2 in axon regeneration. Although glial CNTN2 as well as hypomyelination are dispensable for both neuronal survival and axon regeneration following ONC, the neuronal counterpart comprises a negative regulator of regeneration. Specifically, we reveal a novel mechanism of action for neuronal CNTN2, implicating the inhibition of Akt signalling pathway. The in vitro analysis indicates a BDNF-independent mode of action and biochemical data suggest the implication of the truncated form of TrkB neurotrophin receptor. In conclusion, CNTN2 expressed in CNS neurons serves as an inhibitor of axon regeneration after trauma and its mechanism of action involves the neutralization of Akt-mediated neuroprotective effects.

Microneurotrophin BNN27 Reduces Astrogliosis and Increases Density of Neurons and Implanted Neural Stem Cell-Derived Cells after Spinal Cord Injury

“…Ongoing axonal elongation in the lesion site was evaluated by immunostaining spinal cord parasagittal sections for the L1 cell adhesion molecule that is upregulated in elongating axons [ 36 ] and quantifying the fraction of L1 + pixels in the lesion epicenter and in the dorsal regions rostrally and caudally to the lesion ( Supplementary Materials : Figure S3a ). No difference was observed among the four injured groups in the rostral region and in the lesion epicenter.…”

A novel blood-based epigenetic biosignature in first-episode schizophrenia patients through automated machine learning

“…Then, we employed the multiple UniReD tool [42,43] to identify the functional relationships of respective proteins. Multiple UniReD is a mining tool of published biomedical literature that associates the proteins of interest (query list) to a list of reference proteins that are known and verified to be involved in the disease under investigation (reference list) [44][45][46]. Multiple UniReD produces a score for each protein of interest that signifies its relatedness to the proteins in the reference list.…”

Prediction and Ranking of Biomarkers Using multiple UniReD

“…UniReD parses the references section of UniProt entries for Homo sapiens and Mus musculus organisms and by using the “similar articles” feature of PubMed, it creates clusters of functionally associated proteins [ 19 ]. UniReD performs quite well after following benchmarks against public databases of experimentally verified PPIs and has been used by experimental biologists to identify known and undocumented interactors of protein(s) of interest [ 19 , 20 , 21 ]. In addition, UniReD has been used previously [ 22 , 23 ] for the ranking of biomarkers extracted from high-throughput datasets.…”