Microtubule-based localization of a synaptic calcium-signaling complex is required for left-right neuronal asymmetry in C. elegans.
ABSTRACT 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.
- SourceAvailable from: Michael Levin
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- "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. "
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; 2012:353491. DOI:10.1155/2012/353491
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ABSTRACT: Two main classes of models address the earliest steps of left-right patterning: those postulating that asymmetry is initiated via cilia-driven fluid flow in a multicellular tissue at gastrulation, and those postulating that asymmetry is amplified from intrinsic chirality of individual cells at very early embryonic stages. A recent study revealed that cultured human cells have consistent left-right (LR) biases that are dependent on apical-basal polarity machinery. The ability of single cells to set up asymmetry suggests that cellular chirality could be converted to embryonic laterality by cilia-independent polarity mechanisms in cell fields. To examine the link between cellular polarity and LR patterning in a vertebrate model organism, we probed the roles of apical-basal and planar polarity proteins in the orientation of the LR axis in Xenopus. Molecular loss-of-function targeting these polarity pathways specifically randomizes organ situs independently of contribution to the ciliated organ. Alterations in cell polarity also disrupt tight junction integrity, localization of the LR signaling molecule serotonin, the normally left-sided expression of Xnr-1, and the LR instruction occurring between native and ectopic organizers. We propose that well-conserved polarity complexes are required for LR asymmetry and that cell polarity signals establish the flow of laterality information across the early blastoderm independently of later ciliary functions. genesis 50:219-234, 2012. © 2011 Wiley Periodicals, Inc.genesis 03/2012; 50(3):219-34. DOI:10.1002/dvg.20825
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ABSTRACT: Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway.Science 06/2012; 337(6093):481-4. DOI:10.1126/science.1223899