The axons of C. elegans left and right AWC olfactory neurons communicate at synapses through a calcium-signaling complex to regulate stochastic asymmetric cell identities called AWC(ON) and AWC(OFF). However, it is not known how the calcium-signaling complex, which consists of UNC-43/CaMKII, TIR-1/SARM adaptor protein and NSY-1/ASK1 MAPKKK, is localized to postsynaptic sites in the AWC axons for this lateral interaction. Here, we show that microtubule-based localization of the TIR-1 signaling complex to the synapses regulates AWC asymmetry. Similar to unc-43, tir-1 and nsy-1 loss-of-function mutants, specific disruption of microtubules in AWC by nocodazole generates two AWC(ON) neurons. Reduced localization of UNC-43, TIR-1 and NSY-1 proteins in the AWC axons strongly correlates with the 2AWC(ON) phenotype in nocodazole-treated animals. We identified kinesin motor unc-104/kif1a mutants for enhancement of the 2AWC(ON) phenotype of a hypomorphic tir-1 mutant. Mutations in unc-104, like microtubule depolymerization, lead to a reduced level of UNC-43, TIR-1 and NSY-1 proteins in the AWC axons. In addition, dynamic transport of TIR-1 in the AWC axons is dependent on unc-104, the primary motor required for the transport of presynaptic vesicles. Furthermore, unc-104 acts non-cell autonomously in the AWC(ON) neuron to regulate the AWC(OFF) identity. Together, these results suggest a model in which UNC-104 may transport some unknown presynaptic factor(s) in the future AWC(ON) cell that non-cell autonomously control the trafficking of the TIR-1 signaling complex to postsynaptic regions of the AWC axons to regulate the AWC(OFF) identity.
"AWC asymmetry is stochastic and coordinated, so that 50% of the worms in a population express str-2 in AWCL, while the other 50% express str-2 in AWCR (Troemel et al., 1999; Taylor et al., 2010). The default state of the AWC neurons is AWCOFF, which is specified by a calcium-regulated and microtubule-dependent MAP kinase pathway including UNC-43/CaMKII, TIR-1/Sarm1, NSY-1/MAPKKK, and SEK-1/MAPKK (Figure 2; Sagasti et al., 2001; Tanaka-Hino et al., 2002; Chuang and Bargmann, 2005; Chang et al., 2011). NSY-4 claudin-like protein and NSY-5 gap junction protein act in parallel to inhibit the calcium signaling pathway in the induced AWCON cell (Vanhoven et al., 2006; Chuang et al., 2007). "
[Show abstract][Hide abstract] 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.
"Several recent reviews discuss the numerous molecular pathways that have been implicated in LR patterning in vertebrate and invertebrate phyla (Basu and Brueckner, 2008; Pohl, 2011; Speder et al., 2007; Wood, 2005). In a number of systems including Arabidopsis, Caenorhabditis elegans, snail, and Drosophila , intracellular components such as cytoskeletal and motor protein molecules are involved in very early stages of the establishment of laterality (Chang et al., 2011; Kuroda et al., 2009; Speder et al., 2006; Thitamadee et al., 2002). The involvement of tubulins in this process appears to be widely conserved as well among plant (Arabidopsis), nematode, human cells, and amphibian embryos (Lobikin et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: The earliest steps of left-right (LR) patterning in Xenopus embryos are driven by biased intracellular transport that ensures a consistently asymmetric localization of maternal ion channels and pumps in the first 2-4 blastomeres. The subsequent differential net efflux of ions by these transporters generates a bioelectrical asymmetry; this L:R voltage gradient redistributes small signaling molecules along the LR axis that later regulate transcription of the normally left-sided Nodal. This system thus amplifies single cell chirality into a true left-right asymmetry across multi-cellular fields. Studies using molecular-genetic gain- and loss-of-function reagents have characterized many of the steps involved in this early pathway in Xenopus. Yet one key question remains: how is the chiral cytoskeletal architecture interpreted to localize ion transporters to the left or right side? Because Rab GTPases regulate nearly all aspects of membrane trafficking, we hypothesized that one or more Rab proteins were responsible for the directed, asymmetric shuttling of maternal ion channel or pump proteins. After performing a screen using dominant negative and wildtype (overexpressing) mRNAs for four different Rabs, we found that alterations in Rab11 expression randomize both asymmetric gene expression and organ situs. We also demonstrated that the asymmetric localization of two ion transporter subunits requires Rab11 function, and that Rab11 is closely associated with at least one of these subunits. Yet, importantly, we found that endogenous Rab11 mRNA and protein are expressed symmetrically in the early embryo. We conclude that Rab11-mediated transport is responsible for the movement of cargo within early blastomeres, and that Rab11 expression is required throughout the early embryo for proper LR patterning.
Mechanisms of development 01/2013; 130(4-5). DOI:10.1016/j.mod.2012.11.007 · 2.44 Impact Factor
"It is possible that subtle differences in the bioelectrical patterning signals of the visual system, along with asymmetries of brain and cognitive processing, are involved in establishing these behavioral and functional asymmetries. In C. elegans, for example, a stochastic lateral inhibition system involving ion channels results in lateralized neural differentiation and function     . It is tempting to speculate that this asymmetric bioelectric signal could trigger differential genetic, chemical, and/or biophysical patterns that overlay upon the universal eye development pattern allowing the left and right sides of the visual system to develop differing visual functionality. "
[Show abstract][Hide abstract] ABSTRACT: Consistent left-right asymmetry in organ morphogenesis is a fascinating aspect of bilaterian development. Although embryonic patterning of asymmetric viscera, heart, and brain is beginning to be understood, less is known about possible subtle asymmetries present in anatomically identical paired structures. We investigated two important developmental events: physiological controls of eye development and specification of neural crest derivatives, in Xenopus laevis embryos. We found that the striking hyperpolarization of transmembrane potential (V(mem)) demarcating eye induction usually occurs in the right eye field first. This asymmetry is randomized by perturbing visceral left-right patterning, suggesting that eye asymmetry is linked to mechanisms establishing primary laterality. Bilateral misexpression of a depolarizing channel mRNA affects primarily the right eye, revealing an additional functional asymmetry in the control of eye patterning by V(mem). The ATP-sensitive K(+) channel subunit transcript, SUR1, is asymmetrically expressed in the eye primordia, thus being a good candidate for the observed physiological asymmetries. Such subtle asymmetries are not only seen in the eye: consistent asymmetry was also observed in the migration of differentiated melanocytes on the left and right sides. These data suggest that even anatomically symmetrical structures may possess subtle but consistent laterality and interact with other developmental left-right patterning pathways.
Stem cell International 12/2012; 2012(1):353491. DOI:10.1155/2012/353491 · 2.81 Impact Factor
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