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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. | ỊFEBS Journal Two conserved regions within the tissue-type plasminogen activator gene promoter mediate regulation by brain-derived neurotrophic factor Philip B. Daniel1 Wolfram Lux2 Andre L. Samson1 Wolf-Dieter Schleuning2 f Be eri Niego1 Thomas W. Weiss1 Anna Tjarnlund-Wolf3 and Robert L. Medcalf1 1 Monash University Australian Centre for Blood Diseases Melbourne Australia 2 Research Laboratories at Schering AG Berlin Germany 3 Institute of Neuroscience and Physiology Section for ClinicalNeuroscience and Rehabilitation Sahlgrenska Academy at Goteborg University Sweden Keywords brain-derived neurotrophic factor cortical neurons promoter tissue-type plasminogen activator transcription Correspondence R. L. Medcalf Monash University Australian Centre for Blood Diseases Level 6 Burnet Building 89 CommercialRoad Melbourne 3004 Australia Fax 61 39903 0228 Tel 61 39903 0133 E-mail Robert.medcalf@med.monash.edu.au Present address Schering Germany BU Oncology Berlin Germany fKAIROSmed GmbH Berlin Germany Received 17 December 2006 revised 11 February 2007 accepted 7 March 2007 doi 10.1111 j.1742-4658.2007.05777.x Tissue-type plasminogen activator t-PA has recently been identified as a modulator of neuronal plasticity and can initiate conversion of the proform 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 .
