title: Plasminogen activator promotes recovery following spinal cord injury.
abstract: Plasminogen activators play an important role in synaptic plasticity associated with the crossed phrenic phenomenon (CPP) and recovery of respiratory function after spinal cord injury. A genetic approach using knockout mice lacking various genes in the plasminogen activator/plasmin system has shown that induction of urokinase plasminogen activator (uPA) is required during the first hour after a C2-hemisection for the acquisition of the CPP response. The uPA knockout mice do not show the structural remodeling of phrenic motor neuron synapses characteristic of the CPP response. As shown here uPA acts in a cell signaling manner via binding to its receptor uPAR rather than as a protease, since uPAR knockout mice or knock-in mice possessing a modified uPA that is unable to bind to uPAR both fail to generate a CPP and recover respiratory function. Microarray data and real-time PCR analysis of mRNAs induced in the phrenic motor nucleus after C2-hemisection in C57Bl/6 mice as compared to uPA knockout mice indicate a potential cell signaling cascade downstream possibly involving β-integrin and Src, and other pathways. Identification of these uPA-mediated signaling pathways may provide the opportunity to pharmacologically upregulate the synaptic plasticity necessary for recovery of phrenic motoneuron activity following cervical spinal cord injury.
authors.affiliation: Department of Biochemistry & Molecular Genetics, and Neuroscience Program, University of Colorado School of Medicine, Aurora, CO 80045, USA. Nicholas.Seeds@ucdenver.edu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seeds
authors.forename: Steve
authors.initials: S
authors.lastname: Mikesell
authors.forename: Rebekah
authors.initials: R
authors.lastname: Vest
authors.forename: Thomas
authors.initials: T
authors.lastname: Bugge
authors.forename: Kristin
authors.initials: K
authors.lastname: Schaller
authors.forename: Kenneth
authors.initials: K
authors.lastname: Minor
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010791:Phrenic Nerve / Q000503:physiopathology; D011485:Protein Binding; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000378:metabolism*
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator