Control elements between-9.5 and-3.0 kb in the human tissue-type plasminogen activator gene promoter direct spatial and inducible expression to the murine brain

Tissue-type plasminogen activator (t-PA) participates in the control of syn aptic plasticity and memory formation in the central nervous system (CNS). Transgenic mice harbouring either 9.5, 3.0 or 1.4 kb of the human t-PA prom oter fused to the LacZ reporter gene were used to assess t-PA promoter-dire cted expression in vivo. The 9.5 kb t-PA promoter directed expression to th e brain, most notably to the dentate gyrus, superior colliculus, hippocampu s, thalamus and piriform cortex. Staining was also observed in the retrospl enial and somatosensory cortex. The 3.0 kb t-PA promoter directed generaliz ed and poorly defined expression to the cortex and hippocampus, while the 1 .4 kb t-PA promoter directed expression selectively to the medial habenula. Intravenous administration of lipopolysaccharide into mice habouring the 9 .5 kb t-PA promoter resulted in an increase in reporter gene activity in th e lateral orbital cortex and thalamus. Results of in vitro transfection exp eriments of NT2 cells with a series of t-PA promoter deletion constructs co nfirmed the presence of regulatory elements throughout the 9.5 kb promoter region. Finally, we describe a cis-acting element related to the NFAT recog nition site that provides a protein-binding site and which may play a role in the selective expression of the 1.4 t-PA promoter in the medial habenula . These results indicate that elements between -3.0 and -9.5 kb of the t-PA promoter confer constitutive and inducible expression to specific regions of the CNS.