Activation and repression of activity -dependent expression of brain-derived neurotrophic factor (BDNF).

摘要

In addition to its functions in promoting neuronal survival during development, brain-derived neurotrophic factor (BDNF) has been implicated in modulating activity-dependent synaptic structures and functions in mature neurons. Likewise, the robust induction of BDNF mRNA by neuronal activity supports the hypothesis that BDNF may function as a pertinent modulator of synaptic plasticity. Therefore, a thorough investigation of the molecular mechanisms that govern activity-dependent transcriptional regulation of BDNF may be important to our understanding of activity-regulated neuronal plasticity.;Detailed promoter analysis revealed that BDNF promoter III is regulated by a CREB family protein through binding to the CRE element. In addition, an upstream region located 5' to the CRE element is also required for activity-regulated transcription from BDNF promoter III, and a protein, CaRF, that binds to this upstream region had been identified.;In the first part of the thesis (Chapter III), I describe experiments that demonstrate that the upstream region within BDNF promoter III actually consists of two separate transcriptional elements. One of these two elements, CaRE1, binds a novel transcription factor, CaRF. The other element, CaRE2, is an E-box element that binds the bHLH family transcription factors, the upstream stimulatory factors (USF1 and USF2). I then showed that the USFs are required for activity-dependent transcriptional regulation of BDNF promoter III activity. I also observed that the transcriptional activity of the USFs is regulated by Ca2+-activated signaling pathways in neurons and that the USFs bind to the promoters of a number of neuronal activity-regulated genes in vivo. Together, these findings suggest that, in addition to regulating activity-dependent expression of BDNF, the bHLH family proteins USFs function as general transcription activators of activity-dependent transcription in neurons.;In the second part of the thesis (Chapter IV), I examined the role of a global transcriptional repressor, the methylated CpG binding protein, MeCP2, in the regulation of BDNF promoter III-dependent transcription.;In the final chapter (Chapter V), I discuss the significance of the transcription activators CREB, USFs and CaRF as well as the repressor MeCP2 with respect to activity-dependent neuronal plasticity. In addition, I propose several directions that might facilitate the elucidation of the molecular mechanisms of activity-regulated expression of BDNF. (Abstract shortened by UMI.).