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Volume 17, Number 23, Issue of December 1, 1997 pp. 8984-8996
Expression of Neuroserpin, an Inhibitor of Tissue Plasminogen Activator, in the Developing and Adult Nervous System of the Mouse
Received April 22, 1997; revised Sept. 15, 1997; accepted Sept. 17, 1997.
Stefan R. Krueger1, Gian-Piero Ghisu1, Paolo Cinelli1, Thomas P. Gschwend1, Thomas Osterwalder1, David P. Wolfer2, and Peter Sonderegger1 Departments of 1 Biochemistry and 2 Anatomy, University of Zurich, CH-8057 Zurich, Switzerland
Neuroserpin is a serine protease inhibitor of the serpin family that has been identified as an axonally secreted glycoprotein in neuronal cultures of chicken dorsal root ganglia. To obtain an indication for possible functions of neuroserpin, we analyzed its expression in the developing and the adult CNS of the mouse. In the adult CNS, neuroserpin was most strongly expressed in the neocortex, the hippocampal formation, the olfactory bulb, and the amygdala. In contrast, most thalamic nuclei, the caudate putamen, and the cerebellar granule cells were devoid of neuroserpin mRNA. During embryonic development, neuroserpin mRNA was not detectable in neuroepithelia, but it was expressed in the differentiating fields of most CNS regions concurrent with their appearance. In the cerebellum, the granule cells and a subgroup of Purkinje cells were neuroserpin-positive during postnatal development. As a further step toward the elucidation of neuroserpin function, we performed a study to identify potential target proteases. In vitro, neuroserpin formed SDS-stable complexes and inhibited the amidolytic activity of tissue plasminogen activator, urokinase, and plasmin. In contrast, no complex formation with or inhibition of thrombin was found. Expression pattern and inhibitory specificity implicate neuroserpin as a candidate regulator of plasminogen activators, which have been suggested to participate in the modulation or reorganization of synaptic connections in the adult. During development, neuroserpin may attenuate extracellular proteolysis related to processes such as neuronal migration, axogenesis, or the formation of mature synaptic connections.
Key words: neuroserpin; serine protease inhibitor; plasminogen activator; plasmin; thrombin; central nervous system; synaptogenesis; neuronal plasticity
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