MicroRNAs: regulators of neuronal fate

Abstract

Mammalian neural development has been traditionally studied in the context of evolutionarily conserved signaling pathways and neurogenic transcription factors. Recent studies suggest that microRNAs, a group of highly conserved noncoding regulatory small RNAs also play essential roles in neural development and neuronal function. A part of their action in the developing nervous system is to regulate subunit compositions of BAF complexes (ATP-dependent chromatin remodeling complexes), which appear to have dedicated functions during neural development. Intriguingly, ectopic expression of a set of brain-enriched microRNAs, miR-9/9* and miR-124 that promote the assembly of neuron-specific BAF complexes, converts the nonneuronal fate of human dermal fibroblasts towards postmitotic neurons, thereby revealing a previously unappreciated instructive role of these microRNAs. In addition to these global effects, accumulating evidence indicates that many microRNAs could also function locally, such as at the growth cone or at synapses modulating synaptic activity and neuronal connectivity. Here we discuss some of the recent findings about microRNAs' activity in regulating various developmental stages of neurons.

Figure 1

A model of neuronal reprogramming mediated by miR-9/9*-124 and neurogenic factors. MiR-9/9* and miR-124 in non-neuronal cells are repressed synergistically by neurogenic repressors such as REST complex, non-neuronal BAF complexes and others. The top panel is an example of REST repressing neuronal genes such as miR-9/9* and miR-124. Forced expression of miR-9/9* and miR-124 results in the break of genetic network involving repression of multiple factors including REST complexes, BAF53a, and PTBP1, which normally suppress neurogenesis. The synergism of miRNAs suggests that these miRNAs work programmatically on multiple targets during the process of neuronal conversion. In addition, it is possible that miRNAs may target factors whose silencing potentiates the activity of neurogenic transcription factors (NFs) (bottom panel).

Figure 2

A hypothetical scheme of production of subtype-specific neurons by reprogramming. Leveraging on the known pan-neuronal activity of miR-9/9* and miR-124, additional miRNAs specific to neuronal subtypes may lead to neuronal reprogramming into their respective neuronal subclasses.