microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus

Abstract

Newborn neurons in the dentate gyrus of the adult hippocampus rely upon cAMP response element binding protein (CREB) signaling for their differentiation into mature granule cells and their integration into the dentate network. Among its many targets, the transcription factor CREB activates expression of a gene locus that produces two microRNAs, miR-132 and miR-212. In cultured cortical and hippocampal neurons, miR-132 functions downstream from CREB to mediate activity-dependent dendritic growth and spine formation in response to a variety of signaling pathways. To investigate whether miR-132 and/or miR-212 contribute to the maturation of dendrites in newborn neurons in the adult hippocampus, we inserted LoxP sites surrounding the miR-212/132 locus and specifically targeted its deletion by stereotactically injecting a retrovirus expressing Cre recombinase. Deletion of the miR-212/132 locus caused a dramatic decrease in dendrite length, arborization, and spine density. The miR-212/132 locus may express up to four distinct microRNAs, miR-132 and -212 and their reverse strands miR-132* and -212*. Using ratiometric microRNA sensors, we determined that miR-132 is the predominantly active product in hippocampal neurons. We conclude that miR-132 is required for normal dendrite maturation in newborn neurons in the adult hippocampus and suggest that this microRNA also may participate in other examples of CREB-mediated signaling.microRNA-212 | neurogenesis | plasticity | learning

TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes

“…The knockout of Dicer specifically in postmitotic postnatal motor neurons in mice induces locomotor dysfuction due to the presence of a reduced number of motor neurons (30), indicating that a subset of miRNAs is essential for long-term survival of spinal motor neurons. Among the TDP-43-regulated miRNAs identified in this study, miR-132-3p is highly enriched in neurons and promotes neuronal outgrowth in vitro and in vivo by reducing the levels of the GTPase-activating protein, p250GAP (26,27). In this study, we demonstrated that the attenuation of neuronal outgrowth induced by TDP-43 depletion in differentiated Neruo2a cells can be attributed, at least in part, to the reduced expression of miR-132-3p and miR-132-5p induced by the loss of nuclear TDP-43 function.…”

“…S23 A-D). Considering that miR-132-3p is known to promote neuronal outgrowth in vitro and in vivo (26,27), we examined whether cotransfection of miRNAs could rescue the inhibited neurite outgrowth induced by TDP-43 depletion (Fig. 5 C-E).…”

Epigenetic Mechanisms in Stroke and Epilepsy

“…Moreover, microRNAs achieve spatial specificity of gene expression in that they can regulate mRNA translation locally in the synaptodendritic compartment in an activity-dependent manner (Schratt, 2009b). As an example, miR-132 is critical for hippocampal spine formation and the inflammatory response (Shaked et al, 2009;Magill et al, 2010). miR-132 is thought to function together with FMRP to regulate translation in dendrites.…”

Manipulating MicroRNAs in Murine Models: Targeting the Multi-Targeting in Epilepsy

“…cluding miR-132 and miR-134 target transcripts encoding proteins crucial to growth and remodeling of dendrites, thereby regulating synaptic strength and plasticity (19)(20)(21). MicroRNAs miR-9 and miR-124 target mRNAs involved in neurogenesis and integration of newborn neurons into the circuitry of the mature brain (22,23).…”