Transcriptional Activation of the Human Brain-derived Neurotrophic Factor Gene Promoter III by Dopamine Signaling in NT2/N Neurons

Hung Fang,Joanne Chartier,Caroline Sodja,Angele Desbois,Maria Ribecco-Lutkiewicz,P.Roy Walker,Marianna Sikorska

doi:10.1074/jbc.m211539200

Abstract

We have identified a functional cAMP-response element (CRE) in the human brain-derived neurotrophic factor (BDNF) gene promoter III and established that it participated in the modulation of BDNF expression in NT2/N neurons via downstream signaling from the D1 class of dopamine (DA) receptors. The up-regulation of BDNF expression, in turn, produced neuroprotective signals through receptor tyrosine kinase B (TrkB) and promoted cell survival under the conditions of oxygen and glucose deprivation. To our knowledge this is the first evidence showing the presence of a functional CRE in the human BDNF gene and the role of DA signaling in establishing transcriptional competence of CRE in post-mitotic NT2/N neurons. This ability of DA to regulate the expression of the BDNF survival factor has a profound significance for the nigrostriatal pathway, because it indicates the existence of a feedback loop between the neutrophin, which promotes both the maturation and survival of dopaminergic neurons, and the neurotransmitter, which the mature neurons ultimately produce and release.

Highlights

Brain-derived neurotrophic factor (BDNF)1 is a member of neurotrophin family, structurally related to nerve growth factor, neurotrophin-3, and neurotrophin-4/5
We have identified a functional cyclic AMP (cAMP)-response element (CRE) in the human brain-derived neurotrophic factor (BDNF) gene promoter III and established that it participated in the modulation of BDNF expression in Ntera2/D1 teratocarcimona (NT2)/N neurons via downstream signaling from the D1 class of dopamine (DA) receptors
The up-regulation of BDNF expression, in turn, produced neuroprotective signals through receptor tyrosine kinase B (TrkB) and promoted cell survival under the conditions of oxygen and glucose deprivation. To our knowledge this is the first evidence showing the presence of a functional CRE in the human BDNF gene and the role of DA signaling in establishing transcriptional competence of CRE in postmitotic NT2/N neurons

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) is a member of neurotrophin family, structurally related to nerve growth factor, neurotrophin-3, and neurotrophin-4/5. In contrast to a large body of work on the temporal and spatial patterns of BDNF expression in neurodevelopment and neurodegeneration, relatively little is known about the transcriptional regulation of the human BDNF gene This is partially due to the fact that the genomic structure of the human gene has not yet been fully elucidated. Two transcription factors, CREB and a calciumresponsive factor, were identified as positive regulators of the rat promoter III [23,24,25], and the neuron-restrictive silencer factor as a negative regulator of promoters I and II [20, 26] It is still not known whether the regulatory machinery controlling the rat BDNF gene is conserved in humans

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Conclusion