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Plasminogen Activator Promotes Recovery Following Spinal Cord Injury

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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.

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Acknowledgments

The authors greatly appreciate the excellent assistance of Karin Layton. These studies were supported in part by a grant from NIH-NS044129 to NWS.

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Genetics, and Neuroscience Program, University of Colorado School of Medicine, MS-8315, P.O. Box 6511, Aurora, CO, 80045, USA

    Nicholas Seeds, Steve Mikesell, Rebekah Vest, Kristin Schaller & Kenneth Minor

  2. National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA

    Thomas Bugge

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  1. Nicholas Seeds
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  2. Steve Mikesell
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  3. Rebekah Vest
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  4. Thomas Bugge
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  5. Kristin Schaller
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  6. Kenneth Minor
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Corresponding author

Correspondence to Nicholas Seeds.

Additional information

This research contribution is dedicated to the memory of a dear friend and mentor Marshall W. Nirenberg, who always said don’t be afraid to explore the big questions in science.

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Seeds, N., Mikesell, S., Vest, R. et al. Plasminogen Activator Promotes Recovery Following Spinal Cord Injury. Cell Mol Neurobiol 31, 961–967 (2011). https://doi.org/10.1007/s10571-011-9701-6

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  • DOI: https://doi.org/10.1007/s10571-011-9701-6

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