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.
|Pages (from-to)||2411 - 2423|
|Number of pages||13|
|Publication status||Published - 2007|
Daniel, P. B., Lux, W., Samson, A. L., Schleuning, W-D., Niego, B., Weiss, T. W., Tjarnlung-Wolf, A., & Medcalf, R. L. (2007). Two conserved regions within the tissue-type plasminogen activator gene promoter mediate regulation by brain-derived neurotrophic factor. FEBS Journal, 274(9), 2411 - 2423. https://doi.org/10.1111%2Fj.1742-4658.2007.05777.x