Affiliations: Department of Neurology, Uniformed Services University
of the Health Sciences, Bethesda, MD, USA | Section on Molecular Genetics, Laboratory of
Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National
Institutes of Health, Rockville, MD, USA
Note: [] Corresponding author: Robert H. Lipsky, Ph.D., Laboratory of
Neurogenetics, National Institute on Alcoholism and Alcohol Abuse, National
Institutes of Health, 12420 Parklawn Drive, Suite 451, Rockville, MD 20852,
USA. Tel.: +1 301 402 5591; E-mail: rlipsky@mail.nih.gov
Abstract: Purpose: 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-κB) 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-κB 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-κB-dependent pathway and extended the finding to show that
NF-κB 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.
