NEURAL DEVELOPMENT, regeneration and learning in mammals requires that neurons migrate from germinative zones to their proper place within the nervous system, and often extend axons over very long distances to find their appropriate synaptic targets. A variety of cell recognition, adhesion and repulsion events occur during this process. The involvement of extracellular proteases in these events, as well as in neural tissue remodeling are being studied. The extracellular protease plasminogen activator (PA) is synthesized and secreted by migrating neurons, and can be localized to the axonal growth cone, where it is bound with high affinity to specific receptors in both the central (CNS) and peripheral nervous (PNS) system. In the PNS PA-system components are induced during nerve regeneration, and required for timely recovery of nerve function. Furthermore, PA's may promote axonal regrowth in the lesioned dorsal column of the spinal cord.
Synaptic Plasticity in the adult mouse during cerebellar motor learning of a complex behavioral task involves tissue plasminogen activator activity in synaptic remodeling. Similarly, gene-knockout mice show us that PA plays a role in synaptic plasticity associated with the crossed-phrenic nerve phenomenon of functional recovery of motor neuron activity in the injured spinal cord. We are actively pursuing the molecular mechanisms of PA action in promoting these synaptic changes in both the cerebellum and spinal cord.
On-going studies are assessing functionality of the PA/plasmin system in clearing amyloid-beta peptide from the Alzheimer disease brain, and the ability of the motoneuron trophic factor HGF as a suitable therapy for the treatment of ALS motoneuron disease.
(For more info on tPA, see
http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?173370)
Representative Publications:
Seeds, N.W., B. Williams and P. Bickford (1995). Cerebellar motor learning induces tissue plasminogen activator expression in Purkinje neurons. Science 270, 1992-1994.
Friedman, G.C. and N.W. Seeds (1995). Tissue plasminogen activator mRNA expression in granule neurons coincides with their migration
in the developing cerebellum. J. Comp. Neurol. 360, 658-670.
Hayden, S.M. and N.W. Seeds (1996). Modulated expression of plasminogen activator system components in cultured cells from
dissociated mouse dorsal root ganglia.J.Neuroscience 16, 2307-2317.
Thewke, D. and N.W. Seeds (1996). Expression of hepatocyte
growth factor/scatter factor, its receptor c-met & tPA in the
developing olfactory system. J. Neuroscience 16, 6933-6944.
Thewke, D, and N.W. Seeds (1998). Expression of mRNAs for HGF/SF, c-met, and tPA show a systematic relationship in the developing & adult cerebral cortex and hippocampus. Brain Res. 821, 356-367.
Seeds, N.W., S. Haffke and M. Basham (1999). Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. Proc. Nat. Acad. Sci. USA 96, 14118-14123.
Tabrizi,P., L. Wang, N.W. Seeds, et al. (1999). tPA deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model. Atheroscl.Thromb.& Vas.Biol. 19, 2801-2806.
Basham, M.E. and N.W. Seeds (2001). Plasminogen expression in the neonatal and adult mouse brain J. Neurochem. 77:318-325.
Siconolfi, L.B. and N.W. Seeds (2001). Induction of the plasminogen activator system accompanies peripheral nerve regeneration after sciatic nerve crush. J. Neurosci. 21:4336-4347.
Siconolfi, L.B. and N.W. Seeds (2001). Mice lacking tPA, uPA or plasminogen genes showed delayed functional recovery after sciatic nerve crush. J. Neurosci. 21:4348-4355.
Seeds, N.W., M.E. Basham and J.E. Ferguson (2003). Absence of tissue plasminogen activator gene or activity impairs mouse cerebellar motor learning. J. Neurosci. 23 , 7368-7375.
Siconolfi, L.B. and N.W. Seeds (2003). Mice lacking tPA or uPA genes showed attentuated MMP activity after sciatic nerve crush. J. Neurosci. Res. 74, 430-434.
Minor, K.H., L.K. Akison, H.G. Goshgarian and N.W. Seeds (2006). Spinal cord injury-induced plasticity in the mouse - The crossed phrenic phenomenon. Exp. Neurol. 200, 486-495.
Minor,K.H. and N.W. Seeds (2007). Plasminogen activator induction facilitates recovery of respiratory function following spinal cord injury. Mol. Cell. Neurosci. 37, 143-152.
Fabbro, S. and N.W. Seeds (2008). Tissue Plasminogen Activator Activity is Dramatically Reduced while Neuroserpin is up-regulated in the Alzheimer Disease Brain (submitted)
Minor, K.H. and N.W. Seeds(2008). Plasminogen activator facilitates DRG axonal regeneration on CNS myelin substrates. (submitted)
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