Yu R et al. (2016) Cell "CSR-1 Slices a Balance."

Yu R, Moazed D

[Cell, 2016]

CSR-1 is a germline-expressed C. elegans Argonaute protein essential for viability. In this issue of Cell, Gerson-Gurwitz et al. now demonstrate a role for CSR-1 and its slicer activity in downregulating the levels of maternally deposited mRNAs to fine-tune the expression of proteins with critical roles in embryonic cell divisions.

Yu, A. et al. (2017) International Worm Meeting "Non-associative learning as a behavioral strategy to promote dispersal."

Yu, A., Rankin, C., Ardiel, E.

[International Worm Meeting, 2017]

Habituation is a form of non-associative learning defined as decremented likelihood and/or magnitude in response to repeatedly presented stimuli. Habituation is thought to help animal ignore recurring innocuous events and free up its neural resources to attend to other novel or salient stimuli in the environment. C. elegans is known to habituate to harmless stimuli such as non-localized tap (Rankin et al., 1990). Recently, we have reported that worms also displayed behavioral characteristics of habituation when a pair of nociceptor neurons, ASH, were repeatedly stimulated with optogenetics (Ardiel et al., 2016). Because ASH detects natural aversive stimuli that are harmful and potentially lethal to worms, it seems puzzling that animals habituate to these noxious stimuli. Our analysis used a non-response-centric approach and found that habituation of ASH-mediated reversal responses are accompanied by the simultaneous sensitization of forward locomotion (Ardiel et al., 2017, unpublished). This behavioral plasticity was found to be mediated by the Pigment Dispersal Factor (PDF) signaling pathway. These coordinated changes in different behavioral components form an optimal behavioral strategy to guide animals to spend less time responding to the recurrent noxious stimuli and more time moving away from them. In this present study, we investigated whether tap habituation was associated with changes in other behavioral components. We observed similar patterns of behavioral plasticity in tap habituation that is also mediate by PDF signaling. Our findings suggest that different forms of non-associative learning participate in a suite of coordinated behavioral changes that together promote a shift in behavioral strategy. Our study also highlights the needs for more detailed behavioral analyses.

Yu J et al. (2017) eNeuro "An Aversive Response to Osmotic Upshift in Caenorhabditis elegans."

Hao Y, Yu J, Zhang Y, Yang W, Liu H

[eNeuro, 2017]

Environmental osmolarity presents a common type of sensory stimulus to animals. While behavioral responses to osmotic changes are important for maintaining a stable intracellular osmolarity, the underlying mechanisms are not fully understood. In the natural habitat of Caenorhabditis elegans, changes in environmental osmolarity are commonplace. It is known that the nematode acutely avoids shocks of extremely high osmolarity. Here, we show that C. elegans also generates gradually increased aversion of mild upshifts in environmental osmolarity. Different from an acute avoidance of osmotic shocks that depends on the function of a transient receptor potential vanilloid channel, the slow aversion to osmotic upshifts requires the cGMP-gated sensory channel subunit TAX-2. TAX-2 acts in several sensory neurons that are exposed to body fluid to generate the aversive response through a motor network that underlies navigation. Osmotic upshifts activate the body cavity sensory neuron URX, which is known to induce aversion upon activation. Together, our results characterize the molecular and cellular mechanisms underlying a novel sensorimotor response to osmotic stimuli and reveal that C. elegans engages different behaviors and the underlying mechanisms to regulate responses to extracellular osmolarity.

Yu CJ et al. (2020) Elife "Expansion microscopy of C. elegans."

Haspel G, Sinha A, Hobert O, Asano S, Chen F, Yu CJ, Barry NC, Goodman MB, Boyden ES, Wassie AT, Zhang C, Bhattacharya A

[Elife, 2020]

We recently developed expansion microscopy (ExM), which achieves nanoscale-precise imaging of specimens at ~70 nm resolution (with ~4.5x linear expansion) by isotropic swelling of chemically processed, hydrogel-embedded tissue. ExM of <i>C. elegans</i> is challenged by its cuticle, which is stiff and impermeable to antibodies. Here we present a strategy, expansion of <i>C. elegans</i> (ExCel), to expand fixed, intact <i>C. elegans</i>. ExCel enables simultaneous readout of fluorescent proteins, RNA, DNA location, and anatomical structures at resolutions of ~65-75 nm (3.3-3.8x linear expansion). We also developed epitope-preserving ExCel, which enables imaging of endogenous proteins stained by antibodies, and iterative ExCel, which enables imaging of fluorescent proteins after 20x linear expansion. We demonstrate the utility of the ExCel toolbox for mapping synaptic proteins, for identifying previously unreported proteins at cell junctions, and for gene expression analysis in multiple individual neurons of the same animal.

Yu G et al. (2019) Int J Mol Sci "The Epigenetics of Aging in Invertebrates."

Yang M, Chen M, Gao Y, Wu Q, Yu G

[Int J Mol Sci, 2019]

Aging is an unstoppable process coupled to the loss of physiological function and increased susceptibility to diseases. Epigenetic alteration is one of the hallmarks of aging, which involves changes in DNA methylation patterns, post-translational modification of histones, chromatin remodeling and non-coding RNA interference. Invertebrate model organisms, such as <i>Drosophila melanogaster</i> and <i>Caenorhabditis elegans</i>, have been used to investigate the biological mechanisms of aging because they show, evolutionarily, the conservation of many aspects of aging. In this review, we focus on recent advances in the epigenetic changes of aging with invertebrate models, providing insight into the relationship between epigenetic dynamics and aging.

Yu TW et al. (2001) Nature Neuroscience "Dynamic regulation of axon guidance."

Yu TW, Bargmann CI

[Nature Neuroscience, 2001]

To reach their proper targets, axons rely upon the actions of highly conserved families of attractive and repulsive guidance molecules, including the netrins, Slits, semaphorins and ephrins. These guidance systems are used to generate an astonishingly varied set of neuronal circuits. Here we consider the mechanisms by which a few guidance systems can be used to generate diverse outcomes. Recent studies have revealed extensive transcriptional and post-transcriptional regulation of guidance cues and their regulators, as well as combinatorial mechanisms that integrate information from different families of guidance cues.

Yu, A. et al. (2019) International Worm Meeting "Neuropeptides differentially mediate facilitatory forms of non-associative learning."

Ardiel, E., Rankin, C., Chew, Y. L., Schafer, W., Yu, A.

[International Worm Meeting, 2019]

Sensitization and dishabituation are two forms of facilitatory non-associative learning produced by novel or noxious stimuli, that both increase the likelihood and/or magnitude of a response. Although these two forms of non-associative learning have similar effects on behaviour, previous research suggests that they emerge at different developmental stages and have non-identical electrophysiological profiles. Research into the cellular and molecular mechanisms of sensitization and dishabituation can help to further differentiate the two forms of learning, and provide insight into the relationship between different forms of non-associative learning. Our studies found that neuropeptides differentially mediate sensitization and dishabituation. Using our high-throughput Multi-Worm Tracker in combination with optogenetics, we established paradigms for cross-modal sensitization and dishabituation. We identified a FLP-20/FRPR-3 peptidergic signalling pathway that specifically mediates tap-induced ASH response sensitization but not dishabituation. The PDF neuropeptide system also mediates sensitization and dishabituation of the ASH response, with the possible involvement of a novel receptor. Taken together, our data suggest that a number of neuropeptide systems underlie different forms of non-associative learning. Unravelling the cellular and molecular mechanisms of non-associative learning will further our understanding of behavioural plasticity.

Yu, Hanying (2013) Worm Breeder's Gazette "Snodprot-a protein changing chemotaxis and locomotion of Caenorhabditis elegans"

Yu, Hanying

[Worm Breeder's Gazette, 2013]

Yu Y et al. (2020) ACS Chem Biol "Untargeted Approach for Revealing Electrophilic Metabolites."

Yu Y, Wrobel CJJ, Zhang B, Maxwell DN, Schroeder FC, Curtis BJ, Le HH, Pan JY

[ACS Chem Biol, 2020]

Reactive electrophilic intermediates such as coenzyme A esters play central roles in metabolism but are difficult to detect with conventional strategies. Here, we introduce hydroxylamine-based stable isotope labeling to convert reactive electrophilic intermediates into stable derivatives that are easily detectable <i>via</i> LC-MS. In the model system <i>Caenorhabditis elegans</i>, parallel treatment with ¹⁴NH₂OH and ¹⁵NH₂OH revealed &gt;1000 labeled metabolites, e.g., derived from peptide, fatty acid, and ascaroside pheromone biosyntheses. Results from NH₂OH treatment of a pheromone biosynthesis mutant, <i>acox-1.1</i>, suggested upregulation of thioesterase activity, which was confirmed by gene expression analysis. The upregulated thioesterase contributes to the biosynthesis of a specific subset of ascarosides, determining the balance of dispersal and attractive signals. These results demonstrate the utility of NH₂OH labeling for investigating complex biosynthetic networks. Initial results with <i>Aspergillus</i> and human cell lines indicate applicability toward uncovering reactive metabolomes in diverse living systems.

T Yu et al. (1999) International C. elegans Meeting "Mechanisms of axon pathfinding by SAX-3"

J Zallen, J Hao, W Lim, CI Bargmann, M Tessier-Lavigne, K Prehoda, D Lee, T Yu

[International C. elegans Meeting, 1999]

We are studying the mechanisms by which the axon guidance receptor sax-3 directs axonal outgrowth. sax-3 mutants exhibit a variety of axon phenotypes, including anterior misrouting of axons in the nerve ring, abnormal midline crossing in the ventral cord, and defects in ventrally-directed guidance (e.g. AVM, HSN). sax-3 encodes a transmembrane protein with five immunoglobulin and three fibronectin type III repeats, and has close homologs in flies ( roundabout ) and vertebrates (rat and human Robo1 , Robo2 ). Expression of sax-3 in AVM under the mec-7 promoter rescues its ventral defect, arguing that sax-3 acts as a receptor. What is the signal to which sax-3 responds? One candidate is slit , a secreted molecule first identified in a screen for midline CNS mutants in flies. Experiments with a worm homolog of slit demonstrate that high levels of slit expression are found in regions avoided by sax-3 -dependent axons. In particular, slit is expressed strongly in dorsal, but not ventral, body wall muscle, and in epidermal cells that lie at the anterior boundary of the nerve ring. This expression pattern suggests a model in which sax-3 is a repulsive receptor that directs axons away from sources of slit . In support of this model, misexpression of slit in ventral muscles is sufficient to disrupt AVM ventral growth, an effect which is dependent upon the presence of sax-3 . How does sax-3 elicit changes in growth cone behavior? Binding studies show that a conserved motif in the cytoplasmic domain of sax-3 interacts with enabled, a protein implicated in actin assembly, Listeria motility and cell protrusion. In support of a role of enabled in sax-3 guidance, mutations in unc-34 , a worm homolog of enabled, show strong genetic interactions with sax-3 , in which weak unc-34 alleles dominantly enhance axon defects of a weak sax-3 allele. We have found that a second conserved motif in SAX-3 binds to a C. elegans homolog of dreadlocks , a SH2/SH3 adapter molecule first identified in flies in a screen for axon guidance mutants in the visual system. Currently we are focusing on obtaining more functional evidence for role of unc-34 / ena and dock in sax-3 guidance. These studies may provide a link between guidance events at the membrane and known modulators of the cytoskeleton.