Comprehensive Expression Analyses of Neural Cell-Type-Specific miRNAs Identify New Determinants of the Specification and Maintenance of Neuronal Phenotypes

Abstract

MicroRNAs (miRNAs) have been shown to play important roles in both brain development and the regulation of adult neural cell functions. However, a systematic analysis of brain miRNA functions has been hindered by a lack of comprehensive information regarding the distribution of miRNAs in neuronal versus glial cells. To address this issue, we performed microarray analyses of miRNA expression in the four principal cell types of the CNS (neurons, astrocytes, oligodendrocytes, and microglia) using primary cultures from postnatal d 1 rat cortex. These analyses revealed that neural miRNA expression is highly cell-type specific, with 116 of the 351 miRNAs examined being differentially expressed fivefold or more across the four cell types. We also demonstrate that individual neuron-enriched or neuron-diminished RNAs had a significant impact on the specification of neuronal phenotype: overexpression of the neuron-enriched miRNAs miR-376a and miR-434 increased the differentiation of neural stem cells into neurons, whereas the opposite effect was observed for the glia-enriched miRNAs miR-223, miR-146a, miR-19, and miR-32. In addition, glia-enriched miRNAs were shown to inhibit aberrant glial expression of neuronal proteins and phenotypes, as exemplified by miR-146a, which inhibited neuroligin 1-dependent synaptogenesis. This study identifies new nervous system functions of specific miRNAs, reveals the global extent to which the brain may use differential miRNA expression to regulate neural cell-type-specific phenotypes, and provides an important data resource that defines the compartmentalization of brain miRNAs across different cell types.

MicroRNAs in neural development: from master regulators to fine-tuners

“…Indeed, the global monitoring of miRNA expression during neurogenesis in vivo has identified timespecific (Barca-Mayo and De Pietri Tonelli, 2014;Lv et al, 2014;Miska et al, 2004;Nielsen et al, 2009;Yao et al, 2012), spatially restricted (ventral midline/midbrain dopaminergic progenitor pool) (Anderegg et al, 2013) or cell type-specific (Paridaen and Huttner, 2014;Ghosh et al, 2014) miRNAs, suggesting that different sets of miRNAs might be involved in neuronal versus glial differentiation. This is supported by the finding that 116 miRNAs (out of 351) are differentially expressed in primary cultures enriched for neurons, astrocytes, oligodendrocytes and microglia (Jovicic et al, 2013). As we discuss below, these and other findings have highlighted key roles for a number of miRNAs during neurogenesis and gliogenesis, and during the specification of particular neuronal cell types (Fig.…”

Epileptogenesis

“…For example, miR-146a, which is critical for regulation of astrocyte-mediated inflammatory response, is up-regulated in activated astrocytes during epileptogenesis (Aronica et al 2010;Iyer et al 2012;Jovičić et al 2013). miR-132, a miRNA that influences neuronal morphology by increasing dendritic outgrowth and arborization, and participating in regulation of spine density, is enriched in neurons and consistently up-regulated following epileptogenic stimuli (Jovičić et al 2013). Recently, Bot et al (2013) made an attempt to predict the functional impact of changes in miRNA expression during epileptogenesis by analyzing the expression of their potential mRNA targets.…”

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

“…In a cellular model of spinocerebellar ataxia 17 (SCA17), where we had expressed a TATA-binding protein (TBP) with a pathogenic length of CAG repeats, miRNA expression profiling had shown this miRNA to be down-regulated (Roshan et al 2012). We have also found mir-29a to be highly expressed in primary neurons and the adult mouse brain (Jovicic et al 2013). mir-29b expression has also been shown to increase in neuronal cells during cerebral and cortical maturation and in the sympathetic nervous system at a time when these cells are most resistant to apoptosis (Kole et al 2011).…”