Acute adaptive responses of central sensorimotor neurons after spinal cord injury

Abstract

Spinal cord injury (SCI) can be a lifelong, devastating condition for both the patient and the caregiver, with a daunting incidence rate. Still, there are only limited available therapies and the effectiveness of precise regeneration within the central nervous system is minimal throughout postnatal life. Recently, improved regeneration after SCI was seen by manipulating a pathway in sensorimotor neocortices that is involved in phosphorylation of an RNA binding protein (RBP) required for mRNA translation, the Eukaryotic translation initiation factor 4E (eIF4E). Our data identifies rapid molecular alterations of eIF4E in the sensorimotor neocortices 1 and 3 days after a lateral hemisection SCI, used as a model for Brown-Séquard syndrome. The function of an RBP depends on both its distribution sites within the cell and its phosphorylation states. Indeed, we found both to be affected after SCI. There was a distinct subcellular redistribution of eIF4E and phosphorylated-eIF4E was reduced, indicating that the eIF4E's translation was disrupted. Upon identification and analysis of the mRNA cargo of eIF4E in uninjured sensorimotor neocortices, we found that eIF4E binds both Importin-13 (Ipo13) and Parvalbumin (Pv) mRNAs, indicating a role in their translation. Remarkably, eIF4E's interaction with both Ipo13 and Pv mRNAs was disrupted 1 and 3 days after SCI, despite preservation of total Ipo13 and Pv mRNA levels. Finally, we detected a selective loss of expression of both IPO13 and PV proteins in projection neurons of sensorimotor neocortices, as well as their disrupted dendritic polarity. Since IPO13 is predominantly expressed in neocortical projection neurons and PV in a subset of neocortical interneurons, these data suggest a strong acute effect of SCI on neocortical microcircuitry. Taken together, these data indicate that neocortical eIF4E and a subset of mRNAs may be rapidly recruited to translational machinery after SCI to promote adaptive regeneration response of sensorimotor neurons.

Post-transcriptional regulatory elements and spatiotemporal specification of neocortical stem cells and projection neurons

“…Finally, acute traumas can alter functions of distinct regulatory members of mRNA translation. For example spinal cord injury alters mRNA binding signature of EIF4E in neocortical neurons contralateral to the hemisection model (Thompson K, 2010), an initiation factor that in our screen came as part of GO:RNA binding. These data suggest that post-spinal cord injury mRNAs for possible regenerative efforts are acutely present in central neurons, but their translation is disrupted.…”

Intravenous Infusion of Mesenchymal Stem Cells Alters Motor Cortex Gene Expression in a Rat Model of Acute Spinal Cord Injury

“…R ecent studies in spinal cord injury (SCI) have shown that remote regenerative responses in the brain could be induced after SCI, [1][2][3][4][5][6][7][8] as could local responses in the injured spinal cord. [9][10][11] Brain network reorganization is critical for functional recovery after SCI in both nonhuman primate SCI models 12,13 and clinical patients with SCI.…”

“…Gene expression profiling in the brain post-SCI has shown that acute adaptive regenerative responses in the brain were induced after SCI, 1 and that the SCI-induced molecular pathways in the brain may play an important role in recovery from the injury. [1][2][3] However, as gene expression profiling in the brain after intravenous infusion of MSCs post-SCI has not yet been assessed, in this study, genome-wide RNA profiling in the motor cortex was performed following intravenous infusion of MSCs post-SCI induction in a rat model of contused SCI. Moreover, the gene expression signature in the brain that might be associated with the functional improvements induced by the infused MSCs after SCI was explored.…”