BRAIN-DERIVED NEUROTROPHIC FACTOR STIMULATES AP-1 AND CYCLIC AMP-RESPONSIVE ELEMENT DEPENDENT TRANSCRIPTIONAL ACTIVITY IN CENTRAL-NERVOUS-SYSTEM NEURONS

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates survival and apoptosis of several neuronal populati ons. These effects are initiated by high-affinity membrane receptors d isplaying tyrosine kinase activity (trk). However, the intracellular p athways and genetic mechanisms associated with these receptors are lar gely unknown. Here we show that BDNF stimulates API binding activity i n primary cerebellar neurons, This binding corresponds to a functional complex as it is associated with the induction of AP1-dependent trans activation, Application of API partner mRNAs shows an increase in leve ls of c-fos and c-jun mRNAs after BDNF treatment, resulting from an in duction of their promoters. The cis-acting elements by which BDNF stim ulates c-fos transcription were further studied, We show that BDNF imp inges on multiple regulatory elements, including the serum-responsive element, Fos API-like element, and cyclic AMP (cAMP)-responsive elemen t (CRE) sequences, The latter was stimulated without any detectable in crease in cAMP or Ca2+ levels. To confirm that BDNF induces c-fos tran scription independently of the protein kinase A/cAMP pathway, we trans fected a dominant inhibitory mutant of the regulatory subunit of prote in kinase A. The overexpression of this mutant does not affect the c-f os promoter transactivation by BDNF. In summary, we show that BDNF sti mulates AP1- and CRE-dependent transcription through a mechanism that is distinct from the cAMP- and Ca2+-dependent pathways in CNS neurons.