Title

A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex

Student Author(s)

Nikolaos Mellios; Hsien-Sung Huang

GSBS Program

Neuroscience

UMMS Affiliation

Department of Psychiatry, Brudnick Neuropsychiatric Research Institute

Date

7-18-2008

Document Type

Article

Medical Subject Headings

3' Untranslated Regions; Adolescent; Adult; Aged; Base Sequence; Brain-Derived Neurotrophic Factor; Child; Child, Preschool; *Down-Regulation; Female; *Gene Expression Regulation, Developmental; Humans; Infant; Male; MicroRNAs; Middle Aged; Neurons; Prefrontal Cortex; Pregnancy; *Transcription, Genetic

Disciplines

Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology

Abstract

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.

Rights and Permissions

Citation: Hum Mol Genet. 2008 Oct 1;17(19):3030-42. Epub 2008 Jul 15. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

18632683