MicroRNA-132, -134, and -138: a microRNA troika rules in neuronal dendrites

Abstract

Dendritic mRNA transport and local translation in the postsynaptic compartment play an important role in synaptic plasticity, learning and memory. Local protein synthesis at the synapse has to be precisely orchestrated by a plethora of factors including RNA binding proteins as well as microRNAs, an extensive class of small non-coding RNAs. By binding to complementary sequences in target mRNAs, microRNAs fine-tune protein synthesis and thereby represent critical regulators of gene expression at the post-transcriptional level. Research over the last years identified an entire network of dendritic microRNAs that fulfills an essential role in synapse development and physiology. Recent studies provide evidence that these small regulatory molecules are highly regulated themselves, at the level of expression as well as function. The importance of microRNAs for correct function of the nervous system is reflected by an increasing number of studies linking dysregulation of microRNA pathways to neurological disorders. By focusing on three extensively studied examples (miR-132, miR-134, miR-138), this review will attempt to illustrate the complex regulatory roles of dendritic microRNAs at the synapse and their implications for pathological conditions.

Fig. 1

Biogenesis and regulation pathways of dendritic miRNAs. The miRNA gene is transcribed into a primary miRNA transcript (pri-mRNA) which is cleaved by Drosha to generate a hairpin miRNA precursor (pre-miRNA). After nuclear export, the pre-miRNA is cleaved by Dicer to form the double-stranded miRNA duplex. One strand of this duplex, the mature miRNA, is then incorporated into the miRNA-induced silencing complex (miRISC). The miRISC complex can bind to complementary target mRNAs, thereby repressing their translation. This figure depicts those targets that are in turn regulating miRNA expression in neurons (see text for further details)

Fig. 2

Regulation of dendritic complexity and spine morphogenesis by the “miRNA troika”. Dendritic complexity and spine morphology are regulated by miRNAs. Increased miR-132 and miR-134 levels promote neurite growth and branching by targeting p250GAP and Pum2, respectively. Furthermore, dendritic spine morphogenesis is positively regulated by miR-132 through indirect activation of LimK1, whereas the spine size is negatively regulated by miR-134 through inhibition of LimK1 and by miR-138 through inhibition of Apt1