A perspective on the role of class III semaphorin signaling in central nervous system trauma.

Traumatic injury of the central nervous system (CNS) has severe impact on the patients' quality of life and initiates many molecular and cellular changes at the site of insult. Traumatic CNS injury results in direct damage of the axons of CNS neurons, loss of myelin sheaths, destruction of the surrounding vascular architecture and initiation of an immune response. Class III semaphorins (SEMA3s) are present in the neural scar and influence a wide range of molecules and cell types in and surrounding the injured tissue. SEMA3s and their receptors, neuropilins (NRPs) and plexins (PLXNs) were initially studied because of their involvement in repulsive axon guidance. To date, SEMA3 signaling is recognized to be of crucial importance for re-vascularization, the immune response and remyelination. The purpose of this review is to summarize and discuss how SEMA3s modulate these processes that are all crucial components of the tissue response to injury. Most of the functions for SEMA3s are achieved through their binding partners NRPs, which are also co-receptors for a variety of other molecules implicated in the above processes. The most notable ligands are members of the vascular endothelial growth factor (VEGF) family and the transforming growth factor family. Therefore, a second aim is to highlight the overlapping or competing signaling pathways that are mediated through NRPs in the same processes. In conclusion, we show that the role of SEMA3s goes beyond inhibiting axonal regeneration, since they are also critical modulators of re-vascularization, the immune response and re-myelination.

Schwann cells transduced with a lentiviral vector encoding Fgf-2 promote motor neuron regeneration following sciatic nerve injury.

Fibroblast growth factor 2 (FGF-2) is a trophic factor expressed by glial cells and different neuronal populations. Addition of FGF-2 to spinal cord and dorsal root ganglia (DRG) explants demonstrated that FGF-2 specifically increases motor neuron axonal growth. To further explore the potential capability of FGF-2 to promote axon regeneration, we produced a lentiviral vector (LV) to overexpress FGF-2 (LV-FGF2) in the injured rat peripheral nerve. Cultured Schwann cells transduced with FGF-2 and added to collagen matrix embedding spinal cord or DRG explants significantly increased motor but not sensory neurite outgrowth. LV-FGF2 was as effective as direct addition of the trophic factor to promote motor axon growth in vitro. Direct injection of LV-FGF2 into the rat sciatic nerve resulted in increased expression of FGF-2, which was localized in the basal lamina of Schwann cells. To investigate the in vivo effect of FGF-2 overexpression on axonal regeneration after nerve injury, Schwann cells transduced with LV-FGF2 were grafted in a silicone tube used to repair the resected rat sciatic nerve. Electrophysiological tests conducted for up to 2 months after injury revealed accelerated and more marked reinnervation of hindlimb muscles in the animals treated with LV-FGF2, with an increase in the number of motor and sensory neurons that reached the distal tibial nerve at the end of follow-up.

The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain.

In the adult rodent brain, subsets of neurons are surrounded by densely organised extracellular matrix called perineuronal nets (PNNs). PNNs consist of hyaluronan, tenascin-R, chondroitin sulphate proteoglycans (CSPGs), and the link proteins Crtl1 and Bral2. PNNs restrict plasticity at the end of critical periods and can be visualised with Wisteria floribunda agglutinin (WFA). Using a number of antibodies raised against the different regions of semaphorin3A (Sema3A) we demonstrate that this secreted chemorepulsive axon guidance protein is localised to WFA-positive PNNs around inhibitory interneurons in the cortex and several other PNN-bearing neurons throughout the brain and co-localises with aggrecan, versican, phosphacan and tenascin-R. Chondroitinase ABC (ChABC) was injected in the cortex to degrade glycosaminoglycans (GAGs) from the CSPGs, abolishing WFA staining of PNNs around the injection site. Sema3A-positive nets were no longer observed in the area devoid of WFA staining. In mice lacking the link protein Crtl1 in the CNS only vestigial PNNs are present, and in these mice there were no Sema3A-positive PNN structures. A biochemical analysis shows that Sema3A protein binds with high-affinity to CS-GAGs and aggrecan and versican extracted from PNNs in the adult rat brain, and a significant proportion of Sema3A is retrieved in brain extracts that are enriched in PNN-associated GAGs. The Sema3A receptor components PlexinA1 and A4 are selectively expressed by inhibitory interneurons in the cortex that are surrounded by Sema3A positive PNNs. We conclude that the chemorepulsive axon guidance molecule Sema3A is present in PNNs of the adult rodent brain, bound to the GAGs of the CSPGs. These observations suggest a novel concept namely that chemorepulsive axon guidance molecules like Sema3A may be important functional attributes of PNNs in the adult brain.