THE HUMAN SYNAPSIN-II GENE PROMOTER - POSSIBLE ROLE FOR THE TRANSCRIPTION FACTORS ZIF268 EGR-1, POLYOMA ENHANCER ACTIVATOR-3, AND AP2/

Synapsin II is a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic synaptic nerve terminal . Here we report the cloning and sequencing of the 5'-flanking region of the human synapsin II gene. This sequence is very GC-rich and lacks a TATA or CAAT box, Two major transcriptional start sites were mapped . A hybrid gene consisting of the Escherichia coli chloramphenicol ace tyltransferase gene under the control of 837 base pairs of the synapsi n II 5'-upstream region was transfected into neuronal and non-neuronal cells. While reporter gene expression was low in neuroblastoma and no n-neuronal cells, high chloramphenicol acetyltransferase activities we re monitored in PC12 pheochromocytoma cells. However, there was no cor relation between reporter gene expression in the transfected cells and endogenous synapsin II immunoreactivity, Using DNA-protein binding as says we showed that the transcription factors zif268/egr-1, polyoma en hancer activator 3 (PEA3), and AP2 specifically contact the synapsin I I promoter DNA in vitro. Moreover, the zif268/egr-1 protein as well as PEA3 were shown to stimulate transcription of a reporter gene contain ing synapsin II promoter sequences, In the nervous system, zif268/egr- 1 functions as a ''third messenger'' with a potential role in synaptic plasticity. PEA3 is expressed in the brain and its activity is regula ted by proteins encoded from non-nuclear oncogenes, We postulate that zif268/egr-1 and PEA3 couple extracellular signals to long-term respon ses by regulating synapsin II gene expression.