Abstract
Axonal injury is a common cause of neurological dysfunction. Unfortunately, in contrast to axons from the peripheral nervous system, the limited capacity of regeneration of central nervous system (CNS) axons is a major obstacle for functional recovery in patients suffering neurological diseases that involve the subcortical white matter. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. uPAR expression increases after an injury, and signaling through uPAR promotes tissue remodeling. However, it is yet unknown whether uPA binding to uPAR has an effect on axonal recovery in the CNS. Here, we used in vitro and in vivo models of CNS axonal injury to test the hypothesis that uPA binding to uPAR promotes axonal regeneration in the CNS. We found that newly formed growth cones from axons re-emerging from an axonal injury express uPAR and that binding of uPA to this uPAR promotes axonal recovery by a mechanism that does not require the generation of plasmin. Our data indicate that the binding of recombinant uPA or endogenous uPA to uPAR induces membrane recruitment and activation of β1 integrin via the low density lipoprotein receptor-related protein-1 (LRP1), which leads to activation of the Rho family small GTPase Rac1 and Rac1-induced axonal regeneration. Our results show that the uPA/uPAR/LRP1 system is a potential target for the development of therapeutic strategies to promote axonal recovery following a CNS injury.
Highlights
Axonal injury is a common cause of neurological dysfunction
We found that newly formed growth cones from axons re-emerging from an axonal injury express urokinasetype plasminogen activator receptor (uPAR) and that binding of Urokinase-type plasminogen activator (uPA) to this uPAR promotes axonal recovery by a mechanism that does not require the generation of plasmin
It was initially believed that the mechanism underlying this effect is uPA/uPAR-mediated localization of plasmin’s proteolytic activity to the leading edge of the cell [31], it was soon evident that uPA/uPAR interaction with other molecules and receptors on the cell surface and extracellular matrix (ECM) activates cell signaling pathways that promote tissue remodeling, cell motility, invasion, proliferation, and survival by a variety of mechanisms that not always require the generation of plasmin [11, 32]
Summary
Axonal injury is a common cause of neurological dysfunction. in contrast to axons from the peripheral nervous system, the limited capacity of regeneration of central nervous system (CNS) axons is a major obstacle for functional recovery in patients suffering neurological diseases that involve the subcortical white matter. We show that an injury to mature axons induces the expression of uPAR in the filopodia and transition zone of nascent growth cones, and the binding of uPA to uPAR promotes LRP1-mediated membrane recruitment and activation of 1 integrin, followed by 1 integrin-mediated Rac1 activation and Rac1-induced axonal regeneration.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
