Sobrido Cameán, DanielRobledo Sánchez, DiegoRomaus-Sanjurjo, DanielPérez Cedrón, VanessaSánchez Piñón, LauraRodicio Rodicio, María CelinaBarreiro Iglesias, Antón2020-10-272020-10-272020Sobrido-Cameán D, Robledo D, Romaus-Sanjurjo D, Pérez-Cedrón V, Sánchez L, Rodicio MC and Barreiro-Iglesias A (2020) Inhibition of Gamma-Secretase Promotes Axon Regeneration After a Complete Spinal Cord Injury. Front. Cell Dev. Biol. 8:173. doi: 10.3389/fcell.2020.00173http://hdl.handle.net/10347/23453In 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 injuriesengCopyright © 2020 Sobrido-Cameán, Robledo, Romaus-Sanjurjo, Pérez-Cedrón, Sánchez, Rodicio and Barreiro-Iglesias. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these termsAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/NotchGamma-secretaseAxon regenerationGABABaclofenRNA-SeqLampreySpinal cord injuryjournal article10.3389/fcell.2020.001732296-634Xopen access