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Different Manners of Interplay between MicroRNAs and Gene Programs in Neuronal Specification

Liting Sun, Yang Liu and Changgeng Peng

MicroRNA (miRNA) plays a critical role in self-renewal and differentiation of neural stem cells as well as proliferation and specification of neuronal progenitors through regulating spatial and/or temporal expression of its targets. It’s well documented that mutually exclusive or opposing gradient expression pattern of miRNA and its target gene diversifies subtypes of neurons and even specifies distinct functional properties of bilaterally symmetric neurons. Unlike these mechanisms, we recently showed that miR-183-96-182 cluster timely differently shuts off co-expressed transcription factor SHOX2 in the progenitor pool to generate two subtypes of low threshold mechanoreceptor (LTMR) neurons, early close of SHOX2 expression promoting the fate of Aβ slowly adapting (SA) LTMR neurons and late off leading to the identity of Aδ LTMR neurons. It indicates that population sizes of these two LTMR neurons are reversely generated depending on variant abundance of miR-183 cluster in dorsal root ganglion (DRG). This new mechanism of precisely controlling off-time of key specification gene expression by co-expressed miRNA to regulate both the fates and population sizes of subtypes of neurons broads our understanding of how diverse neurons derived from a same progenitor pool are specified by miRNA-regulated gene program, and will potentially help us to efficiently differentiate human iPS cells to one certain type of cells for therapeutics purpose or making drug-screening models. In this commentary, we discuss our recent findings in context of how miRNA interplays with gene programs in four different manners to specify neuronal fates, and propose future directions.