Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: From genes to phenotype.
OBJECTIVE
Brain-derived neurotrophic factor (BDNF) is a member of the family of neurotrophins and promotes diverse effects in neurons including development, maintenance of function, synaptic plasticity, and survival in different animal models. We present advances in our understanding of the genomics of the BDNF gene (bdnf) and its regulation by calcium-activated transcription factors, including cAMP response element binding protein (CREB) and more recently, nuclear factor kappaB (NF-kappaB) and discuss these findings in the context of neuronal plasticity and survival.


METHODS
We used amplified bdnf complementary DNAs (cDNAs) and genomic DNA templates for direct sequencing and sequence variant discovery, information mining of public databases, and conventional molecular and cellular biology approaches to screen bdnf for novel regulatory elements, alternatively spliced exons, and functional sequence variants.


RESULTS
We discovered a candidate NF-kappaB site in promoter 3 of bdnf and showned that activation of N-methyl-D-aspartate (NMDA) inotropic glutamate receptors increased bdnf expression through an NF-kappaB-dependent pathway and extended the finding to show that NF-kappaB was required for NMDA neuroprotection in vitro. In addition, sequence analysis of bdnf cDNAs from different brain regions predicted at least three pre-pro-BDNF protein isoforms, two of which were previously unknown. Each isoform differs at the amino terminus and may have functional importance.


CONCLUSIONS
Given the central role that BDNF plays in the developing and adult nervous system, understanding how BDNF is regulated and how it functions will enhance our knowledge of its diverse effects, which may lead to more effective treatments for neurodegenerative disorders and reveal the role of BDNF in complex phenotypes related to behavior.
Marini
Ann M
AM
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Jiang
Xueying
X
Wu
Xuan
X
Tian
Feng
F
Zhu
Daming
D
Okagaki
Peter
P
Lipsky
Robert H
RH
D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010641:Phenotype
D019208:Brain-Derived Neurotrophic Factor; D016328:NF-kappa B