HMGP - Nicholas Seeds, Ph.D.

Neural development 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 rind their appropriate synaptic targets. A variety of cell recognition, adhesion and repulsion events occur during this process. The involvement of exrtacellular 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 cell-bound urokinase (uPA) directly catalyzes the limited cleavage of extracellular matrix molecules. Thus, PAs are proposed to facilitate cell movement through a dense tissue milieu by the local digestion of cell-matrix and cell-cell adhesion proteins. More general proteolysis is prevented by PA-inhibitors secreted by adjacent glia and synaptic target tissues.

The developmental regulation of gene expression for PAs, their receptors, and their inhibitors is also being studied. In situ hybridization of the embryonic mouse brain shows high levels of tissue plasminogen activator (tPA) mRNA in the rhombencephalon, where there is extensive folding and bending of the developing brain, and where tPA may play a growth factor role. In the neonate tPA MRNA is elevated in cerebellum and olfactory bulb. In the cerebellum, tPA expression is induced as granule cell migration begins, and in the mature animal tPA may play a role in synaptic remodeling associated with complex motor learning.

Developmental Neurobiology: molecular aspects of neuronal migration, neurite outgrowth and motor learning.

Publications

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.

Zlokovic, B.V., Z. Wang, S. Schreiber, M. Fisher and N.W. Seeds (1995). Expression of tissue plasminogen activator and the blood-brain barrier in guinea pigs and rats. Neurosurgery 37, 955-961.

Seeds, N.W., B. Williams and P. Bickford (1995). Cerebellar motor learning induces tissue plasminogen activator expression in Purkinje neurons. Science 270, 1992-1994 .

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.

Seeds, N.W., G. Friedman, A. Krystosek, S. Haffke, S. Hayden, D. Thewke and P. McGuire (1996). Plasminogen activators and extracellular matrix in neuronal development, regeneration and plasticity. Seminars in Neuroscience 8, 405-412.

Thewke, D. and N.W. Seeds (1996). Expression of hepatocyte growth factor/scatter factor, its receptor c-met and tissue plasminogen activator in the developing olfactory system. J. Neuroscience 16, 6933-6944.

Seeds, N.W., L. Siconolfi and S. Haffke (1997). Neuronal extracellular proteases facilitate cell migration, axonal growth and pathfinding. Cell & Tissue Res. 290, 367-370.

Thewke, D, and N.W. Seeds (1998). Expression of mRNAs for HGF/SF, c-met, and tPA show a systematic relationship in the developing and 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. & Vasc. 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.