The MicroRNA mir-71 Inhibits Calcium Signaling by Targeting the TIR-1/Sarm1 Adaptor Protein to Control Stochastic L/R Neuronal Asymmetry in C. elegans

University of California San Diego, United States of America
PLoS Genetics (Impact Factor: 7.53). 08/2012; 8(8):e1002864. DOI: 10.1371/journal.pgen.1002864
Source: PubMed


The Caenorhabditis elegans left and right AWC olfactory neurons communicate to establish stochastic asymmetric identities, AWC(ON) and AWC(OFF), by inhibiting a calcium-mediated signaling pathway in the future AWC(ON) cell. NSY-4/claudin-like protein and NSY-5/innexin gap junction protein are the two parallel signals that antagonize the calcium signaling pathway to induce the AWC(ON) fate. However, it is not known how the calcium signaling pathway is downregulated by nsy-4 and nsy-5 in the AWC(ON) cell. Here we identify a microRNA, mir-71, that represses the TIR-1/Sarm1 adaptor protein in the calcium signaling pathway to promote the AWC(ON) identity. Similar to tir-1 loss-of-function mutants, overexpression of mir-71 generates two AWC(ON) neurons. tir-1 expression is downregulated through its 3' UTR in AWC(ON), in which mir-71 is expressed at a higher level than in AWC(OFF). In addition, mir-71 is sufficient to inhibit tir-1 expression in AWC through the mir-71 complementary site in the tir-1 3' UTR. Our genetic studies suggest that mir-71 acts downstream of nsy-4 and nsy-5 to promote the AWC(ON) identity in a cell autonomous manner. Furthermore, the stability of mature mir-71 is dependent on nsy-4 and nsy-5. Together, these results provide insight into the mechanism by which nsy-4 and nsy-5 inhibit calcium signaling to establish stochastic asymmetric AWC differentiation.

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    • "As with many mutant models, the absence of defects may indicate compensatory mechanisms, but at least in these cases compensation was not brought about by simple replacement of the lost connexin, at least as judged by the loss of a functional GJ pore as revealed by tracer and electrical recordings. Nevertheless, GJ and hemichannel signaling is likely to be critical at many different stages in the life of a neuron and its progenitors, from stem and blast cell proliferation [101] [102] [103], cellular differentiation and migration [49] [104] [105] to cell death [106] [107] [108]. In particular, it is worth mentioning that in the developing brain, neuronal and glial coupling and hemichannel signaling has been suggested to directly regulate cell death/survival mechanisms [109]. "
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    ABSTRACT: Recent evidence indicates that gap junction (GJ) proteins can play a critical role in controlling neuronal connectivity as well as cell morphology in the developing nervous system. GJ proteins may function analogously to cell adhesion molecules, mediating cellular recognition and selective neurite adhesion. Moreover, during synaptogenesis electrical synapses often herald the later establishment of chemical synapses, and thus may help facilitate activity-dependent sculpting of synaptic terminals. Recent findings suggest that the morphology and connectivity of embryonic leech neurons are fundamentally organized by the type and perhaps location of the GJ proteins they express. For example, ectopic expression in embryonic leech neurons of certain innexins that define small GJ-linked networks of cells leads to the novel coupling of the expressing cell into that network. Moreover, gap junctions appear to mediate interactions among homologous neurons that modulate process outgrowth and stability. We propose that the selective formation of GJs between developing neurons and perhaps glial cells in the CNS helps orchestrate not only cellular synaptic connectivity but also can have a pronounced effect on the arborization and morphology of those cells involved.
    FEBS letters 02/2014; 588(8). DOI:10.1016/j.febslet.2014.02.010 · 3.17 Impact Factor
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    • "Furthermore, miRNAs can be localized to subcellular compartments, such as axons, growth cones or synapses, to rapidly alter local gene expression profiles, but not much is known about the transport mechanisms that provide that specificity (Corbin et al., 2009; Natera-Naranjo et al., 2010; Kaplan et al., 2013; Sasaki et al., 2013). The temporally regulated expression of miRNAs within neurons suggests a role in the orderly transition of sequential differentiation events (Johnston and Hobert, 2003; Chang et al., 2004b; Hsieh et al., 2012; Zou et al., 2012, 2013; Chiu and Chang, 2013). Recent evidence indeed showed that miRNAs can provide timing mechanisms for orderly developmental events in neurons (Zou et al., 2012). "
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    ABSTRACT: The assembly of functional neural circuits is critical for complex thoughts, behavior and general brain function. Precise construction of neural circuits requires orderly transition of sequential events from axon outgrowth, pathfinding, branching, to synaptogenesis. Each of these steps is required to be tightly regulated in order to achieve meticulous formation of neuronal connections. MicroRNAs (miRNAs), which silence gene expression post-transcriptionally via either inhibition of translation or destabilization of messenger RNAs, have emerged as key regulators of neuronal connectivity. The expression of miRNAs in neurons is often temporally and spatially regulated, providing critical timing and local mechanisms that prime neuronal growth cones for dynamic responses to extrinsic cues. Here we summarize recent findings of miRNA regulation of neuronal connectivity in a variety of experimental platforms.
    Frontiers in Cellular Neuroscience 01/2014; 7:283. DOI:10.3389/fncel.2013.00283 · 4.29 Impact Factor
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    • "One of the important questions on AWC asymmetry is how the calcium signaling pathway is downregulated by nsy-4 and nsy-5 in the AWCON cell. A recent study showed that the miRNA mir-71 acts downstream of nsy-4 and nsy-5 to promote AWCON in a cell autonomous manner through inhibiting the expression of the calcium signaling adaptor protein gene tir-1 (Figure 2; Hsieh et al., 2012). The TIR-1/Sarm1 adaptor protein assembles a calcium-signaling complex to cell-autonomously specify the default AWCOFF identity (Chuang and Bargmann, 2005). "
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    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.
    Frontiers in Cellular Neuroscience 09/2013; 7:158. DOI:10.3389/fncel.2013.00158 · 4.29 Impact Factor
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