Maturation of the human dorsolateral prefrontal cortex coincides with a dynamic shift in microRNA expression

Abstract

MicroRNA are small RNAs that provide specificity for the RNA induced silencing complex, which forms the basis of an exquisite combinatorial system for posttranscriptional regulation. This system, essential for complex metazoans, is exemplified in the development of the cerebral cortex. To explore the complexity of human cortical miRNA expression in detail, we analyzed RNA from postmortem prefrontal cortex from 97 subjects aged 2 months to 78 years using miRNA microarray. Global miRNA expression was highest in the early years before declining significantly after adolescence (n = 140 decreased, n = 32 increased). Late adolescence was also marked by an inflection point between miRNA on an upward trajectory vs the majority going down. Functional annotation of target genes displaying inverse mRNA expression patterns in the same tissue were overrepresented in neurodevelopmentally significant pathways including neurological disease (most significantly schizophrenia), nervous system development, and cell-to-cell signaling. As mature miRNA expression is largely posttranscriptionally regulated, miRNA biogenesis gene expression was also examined. Dicer and Exportin-5 displayed significant associations with age; however, neither correlated with global miRNA expression across the lifespan. This investigation of cortical miRNA expression provides a framework for understanding the complex posttranscriptional regulatory environment during development and aging that may form a substrate for changes observed in neurodevelopmental disorders.

Keywords: aging; ment; miRNA; neurodevelop‐; prefrontal cortex; schizophrenia.

Fig. 1.

miRNA expression changes in the developing DLPFC. (A) The average expression of 360 miRNA was significantly decreased from the teenage group (13 years) onward. (B) Regardless of increasing/decreasing trajectory over the lifespan, age-associated miRNA were highly correlated until teenage years then proceeded in opposite directions. Bars are shown as the average expression for each developmental group plus standard error.

Fig. 2.

Hierarchical clustering of 180 miRNA displaying age-related expression changes in the DLPFC. Hierarchical clustering was conducted on the 172 altered miRNA. Red = high expression and blue = low expression. Samples are arranged left to right in order of increasing age (years). The distinct change in miRNA levels to either increased or decreased expression occurred at approximately 17 years.

Fig. 3.

The expression of miRNA biogenesis genes across the lifespan. (A) DGCR8 mRNA displayed a 50% reduction from the neonate to infant groups but normalized by adulthood. (B) DROSHA mRNA did not display any age-related changes over the lifespan. (C) DICER mRNA increases over the lifespan, significant from young adulthood onward. (D) Exportin-5 mRNA decreases over the lifespan, significant from teenage years onward. Neonates 0.1–0.2 years, infants 0.3–0.9 years, toddlers 1.6–4.9 years, school age 5.4–12 years, teenage 13–18 years, young adults 20–24.9 years, adults 33–49.2 years, older adults 50–78 years. Bars are average miRNA expression for each developmental group. Error bars are standard error.

Fig. 4.

(A) Clustering of Spearman correlated samples reveals 5 distinct groups of expression. (B) Expression is grouped into infant (cluster 1), young adult (cluster 2), and adult groups (clusters 3–5). The adult clusters are significantly lower in expression that clusters 1 and 2. Bars are average miRNA expression. Error bars are standard error.