microRNA function in left-right neuronal asymmetry: perspectives from C. elegans

Abstract

Left–right asymmetry in anatomical structures and functions of the nervous system is present throughout the animal kingdom. For example, language centers are localized in the left side of the human brain, while spatial recognition functions are found in the right hemisphere in the majority of the population. Disruption of asymmetry in the nervous system is correlated with neurological disorders. Although anatomical and functional asymmetries are observed in mammalian nervous systems, it has been a challenge to identify the molecular basis of these asymmetries. C. elegans has emerged as a prime model organism to investigate molecular asymmetries in the nervous system, as it has been shown to display functional asymmetries clearly correlated to asymmetric distribution and regulation of biologically relevant molecules. Small non-coding RNAs have been recently implicated in various aspects of neural development. Here, we review cases in which microRNAs are crucial for establishing left–right asymmetries in the C. elegans nervous system. These studies may provide insight into how molecular and functional asymmetries are established in the human brain.

Asymmetric neural development in the Caenorhabditis elegans olfactory system

“…a, left cell, step 2) (Chuang et al ., ; Vanhoven et al ., ). (2) microRNAs have been shown to play crucial roles in various aspects of neural development, including neuronal asymmetry (Alqadah et al ., ). The microRNA mir‐71 inhibits the expression of the TIR‐1/Sarm1 adaptor protein by binding to its 3′ UTR (Fig.…”

“…Directional asymmetries have stereotypical asymmetric features on one particular side of an animal; while random asymmetries or antisymmetries have asymmetric features randomly distributed on either the left or right side within a population. The left and right amphid single cilliary ending (ASE) taste neurons develop a directional asymmetry in the expression patterns of chemosensory receptors, which is initiated by Notch signaling in early embryos and is established through transcriptional regulation cascades of microRNAs and transcription factors (Alqadah et al ., ; Cochella and Hobert, ; Hobert, ; Hobert et al ., ). Unlike ASE neurons, the left and right amphid wing “C” (AWC) olfactory neurons exhibit antisymmetric/stochastic expression patterns of chemosensory receptors (Fig.…”

Asymmetric development of the nervous system

“…Whereas ASE neurons display directional asymmetry, AWC neurons show stochastic asymmetry. Directional ASE asymmetry and stochastic AWC asymmetry are established through distinct mechanisms (Sagasti, 2007;Taylor et al, 2010;Alqadah et al, 2013;Alqadah et al, 2014;Hobert, 2014;Hsieh et al, 2014;Alqadah et al, 2016c;Hsieh et al, 2017).…”

“…Downstream of nsy‐4 and nsy‐5 , the AWC OFF fate is also inhibited at the post‐transcriptional level by the miRNA mir‐71 , which targets tir‐1 . Down‐regulation of tir‐1 effectively uncouples UNC‐43 (CaMKII) and NSY‐1 (MAPKKK), thus inhibiting their downstream signaling pathways (Hsieh et al, ; Alqadah et al, ). In addition, the highly conserved HMG‐box transcription factor SOX‐2 also promotes the AWC ON subtype (Alqadah et al, ; Alqadah et al, ).…”

Mechanisms controlling diversification of olfactory sensory neuron classes

“…Voltage- and calcium-activated SLO-1 and SLO-2 BK potassium channels act redundantly downstream of NSY-5 to antagonize calcium channel-mediated signaling in promoting the AWC ON subtype [26]. In addition, the microRNA mir-71 acts downstream of NSY-5 gap junctions and NSY-4 claudins to inhibit TIR-1-mediated calcium signaling to promote the AWC ON subtype [27,28]. Together, these steps lead to suppression of the CaMKII-MAPK signaling cascade, and result in expression of AWC ON -specific genes [29,30].…”