MicroRNA filters Hox temporal transcription noise to confer boundary formation in the spinal cord

Abstract

The initial rostrocaudal patterning of the neural tube leads to differential expression of Hox genes that contribute to the specification of motor neuron (MN) subtype identity. Although several 3′ Hox mRNAs are expressed in progenitors in a noisy manner, these Hox proteins are not expressed in the progenitors and only become detectable in postmitotic MNs. MicroRNA biogenesis impairment leads to precocious expression and propagates the noise of Hoxa5 at the protein level, resulting in an imprecise Hoxa5-Hoxc8 boundary. Here we uncover, using in silico simulation, two feed-forward Hox-miRNA loops accounting for the precocious and noisy Hoxa5 expression, as well as an ill-defined boundary phenotype in Dicer mutants. Finally, we identify mir-27 as a major regulator coordinating the temporal delay and spatial boundary of Hox protein expression. Our results provide a novel trans Hox-miRNA circuit filtering transcription noise and controlling the timing of protein expression to confer robust individual MN identity.

Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

“…All spinal MNs are generated from pMNs, and pMNs are established upon co-expression of Olig2, Nkx6.1 and Nkx6.2 under conditions of high Shh levels [2,105,132,162]. Although a series of miRNAs have been shown to facilitate patterning of the neuronal progenitors in the spinal cord and controlling of MN differentiation [24,25,27,74,141,142], the roles of lncRNAs during MN development are just beginning to emerge. In Table 1, we summarize the importance of lncRNAs for the regulation of transcription factors in MN contexts.…”

microRNA-mediated noise processing in cells: A fight or a game?

“…The first and older idea sees miRNAs playing a pivotal role in gene regulatory networks by reducing fluctuations in protein expression, thus conferring stability to the gene-expression network [19,[39][40][41]. Indeed gene expression may gain precision, thereby stabilising the identity of individual cells, through miRNA-mediated noise filtering [42]. The way miRNAs act as noise buffers is through network motifs [43].…”

From Endogenous to Synthetic microRNA-Mediated Regulatory Circuits: An Overview

“…The FFL is one of the most represented three node network motifs in transcriptional networks [1,101]. Given its role in a wide range of biological processes [102][103][104] and its well established association with diseases (ranging from cancer [17,105,106] to autoimmune diseases [107]), it is currently widely studied. Its general scheme is shown in Figure 2a, where the edges between the nodes represent the interactions between the molecules and may have either an activating or repressing function.…”

“…Later, different works showed an over-representation of FFLs mediated by microRNAs at a genome wide level [11,[109][110][111], highlighting their importance in gene regulatory networks [112]. Specifically, in the case of mammalian genomes, these circuits play crucial roles in cell decision making, proliferation, development, and differentiation [6,[102][103][104][113][114][115], as well as in DNA synthesis control and cell cycle regulation in both normal and cancer cells [111,116,117]. (e,f) Incoherent miRNA mediated feed-forward loops (iFFLs): regulatory paths make an overall negative sign.…”