Two conserved regions within the tissue‐type plasminogen activator gene promoter mediate regulation by brain‐derived neurotrophic factor

Tissue‐type plasminogen activator (t‐PA) has recently been identified as a modulator of neuronal plasticity and can initiate conversion of the pro‐form of brain‐derived neurotrophic factor (BDNF) into its mature form. BDNF also increases t‐PA gene expression implicating t‐PA as a downstream effector of BDNF function. Here we demonstrate that BDNF‐mediated induction of t‐PA mRNA requires an increase in t‐PA gene transcription. Reporter constructs harboring 9.5 kb of the human t‐PA promoter conferred BDNF‐responsiveness in transfected mouse primary cortical neurons. This regulation was recapitulated in HEK 293 cells coexpressing the TrkB neurotrophin receptor. t‐PA promoter‐deletion analysis revealed the presence of two BDNF‐responsive domains, one located between −3.07 and −2.5 kb and the other within the proximal promoter. The upstream region was shown to confer BDNF responsiveness in a TrkB‐dependent manner when attached to a heterologous promoter. We also identify homologous regions within the murine and bovine t‐PA gene promoters and demonstrate that the equivalent upstream murine sequence functions as a BDNF‐responsive enhancer when inserted 5′ of the human proximal t‐PA promoter. Hence, BDNF‐mediated induction of t‐PA transcription relies on conserved modular promoter elements including a novel upstream BDNF‐responsive domain and the proximal t‐PA gene promoter.