A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex.
Expression of brain-derived neurotrophic factor (BDNF) is developmentally regulated in prefrontal cortex (PFC). The underlying molecular mechanisms, however, remain unclear. Here, we explore the role of microRNAs (miRNAs) as post-transcriptional inhibitors of BDNF. A sequential approach involving in silico, miRNA microarray, in situ hybridization and qRT-PCR studies identified a group of 10 candidate miRNAs, segregating into five miRNA families (miR-30a-5p/b/c/d, miR-103/107, miR-191, miR-16/195, miR-495), which exhibited distinct developmental and lamina-specific expression in human PFC. Luciferase assays confirmed that at least two of these miRNAs, miR-30a-5p and miR-195, target specific sequences surrounding the proximal polyadenylation site within BDNF 3'-untranslated region. Furthermore, neuronal overexpression of miR-30a-5p, a miRNA enriched in layer III pyramidal neurons, resulted in down-regulation of BDNF protein. Notably, a subset of seven miRNAs, including miR-30a-5p, exhibited an inverse correlation with BDNF protein levels in PFC of subjects age 15-84 years. In contrast, the role of transcriptional mechanisms was more apparent during the transition from fetal to childhood and/or young adult stages, when BDNF mRNA up-regulation was accompanied by similar changes in (open chromatin-associated) histone H3-lysine 4 methylation at BDNF gene promoters I and IV. Collectively, our data highlight the multiple layers of regulation governing the developmental expression of BDNF in human PFC and suggest that miRNAs are involved in the fine-tuning of this neurotrophin particularly in adulthood.
Mellios
Nikolaos
N
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, 303 Belmont Street, Worcester, MA 01604, USA.
Huang
Hsien-Sung
HS
Grigorenko
Anastasia
A
Rogaev
Evgeny
E
Akbarian
Schahram
S
D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000254:growth & development / Q000378:metabolism*; D011247:Pregnancy; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D019208:Brain-Derived Neurotrophic Factor; D035683:MicroRNAs