Abstract
In a recent study, we showed that GABA and baclofen (a GABAB receptor agonist) inhibit caspase activation and promote axon regeneration in descending neurons of the sea lamprey brainstem after a complete spinal cord injury (Romaus-Sanjurjo et al., 2018a). Now, we repeated these treatments and performed 2 independent Illumina RNA-Sequencing studies in the brainstems of control and GABA or baclofen treated animals. GABA treated larval sea lampreys with their controls were analyzed 29 days after a complete spinal cord injury and baclofen treated larvae with their controls 9 days after the injury. One of the most significantly downregulated genes after both treatments was a HES gene (HESB). HES proteins are transcription factors that are key mediators of the Notch signaling pathway and gamma-secretase activity is crucial for the activation of this pathway. So, based on the RNA-Seq results we subsequently treated spinal cord injured larval sea lampreys with a novel gamma-secretase inhibitor (PF-3804014). This treatment also reduced the expression of HESB in the brainstem and significantly enhanced the regeneration of individually identifiable descending neurons after a complete spinal cord injury. Our results show that gamma-secretase could be a novel target to promote axon regeneration after nervous system injuries.
Highlights
In mammals, including humans, spinal cord injury (SCI) is a devastating event that can lead to permanent disability
We showed that both GABA and baclofen promote axon regeneration after a complete SCI in lampreys (Romaus-Sanjurjo et al, 2018a)
We aimed to identify new genes involved in axon regeneration in lampreys that might be regulated by GABAergic signaling
Summary
In mammals, including humans, spinal cord injury (SCI) is a devastating event that can lead to permanent disability. During recovery from a complete SCI, lampreys are able to regenerate approximately 50% of their brainstem descending neurons and this partial axonal regeneration is needed for recovery (Davis and McClellan, 1994; Jacobs et al, 1997; Cornide-Petronio et al, 2011; Parker, 2017). This offers an interesting vertebrate model to find new signaling pathways responsible for neuronal survival and axon regeneration in descending neurons after SCI.
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