Bretscher AJ et al. (2011) Neuron "Temperature, oxygen, and salt-sensing neurons in C. elegans are carbon dioxide sensors that control avoidance behavior."

Bretscher AJ, Laurent P, Busch KE, Murphy RJ, Kodama-Namba E, De Bono M, Soltesz Z

[Neuron, 2011]

Homeostatic control of body fluid CO(2) is essential in animals but is poorly understood. C. elegans relies on diffusion for gas exchange and avoids environments with elevated CO(2). We show that C. elegans temperature, O(2), and salt-sensing neurons are also CO(2) sensors mediating CO(2) avoidance. AFD thermosensors respond to increasing CO(2) by a fall and then rise in Ca(2+) and show a Ca(2+) spike when CO(2) decreases. BAG O(2) sensors and ASE salt sensors are both activated by CO(2) and remain tonically active while high CO(2) persists. CO(2)-evoked Ca(2+) responses in AFD and BAG neurons require cGMP-gated ion channels. Atypical soluble guanylate cyclases mediating O(2) responses also contribute to BAG CO(2) responses. AFD and BAG neurons together stimulate turning when CO(2) rises and inhibit turning when CO(2) falls. Our results show that C. elegans senses CO(2) using functionally diverse sensory neurons acting homeostatically to minimize exposure to elevated CO(2).

Yang Y et al. (2024) Nucleic Acids Res "COSA-1 mediated pro-crossover complex formation promotes meiotic crossing over in C. elegans."

Wang B, Nan W, Liu G, Yang Y, Hong Y, Gartner A, Zhang H, Wang N

[Nucleic Acids Res, 2024]

Accurate chromosome segregation during meiosis requires the establishment of at least one crossover (CO) between each pair of homologous chromosomes. CO formation depends on a group of conserved pro-CO proteins, which colocalize at CO-designated sites during late meiotic prophase I. However, it remains unclear whether these pro-CO proteins form a functional complex and how they promote meiotic CO formation in vivo. Here, we show that COSA-1, a key component required for CO formation, interacts with other pro-CO factors, MSH-5 and ZHP-3, via its N-terminal disordered region. Point mutations that impair these interactions do not affect CO designation, but they strongly hinder the accumulation of COSA-1 at CO-designated sites and result in defective CO formation. These defects can be partially bypassed by artificially tethering an interaction-compromised COSA-1 derivate to ZHP-3. Furthermore, we revealed that the accumulation of COSA-1 into distinct foci is required to assemble functional 'recombination nodules'. These prevent early CO-designated recombination intermediates from being dismantled by the RTEL-1 helicase and protect late recombination intermediates, such as Holliday junctions, until they are resolved by CO-specific resolvases. Altogether, our findings provide insight into COSA-1 mediated pro-CO complex assembly and its contribution to CO formation.

Kodama-Namba E et al. (2013) PLoS Genet "Cross-modulation of homeostatic responses to temperature, oxygen and carbon dioxide in C. elegans."

Fenk LA, Gross E, Bretscher AJ, Busch KE, De Bono M, Kodama-Namba E

[PLoS Genet, 2013]

Different interoceptive systems must be integrated to ensure that multiple homeostatic insults evoke appropriate behavioral and physiological responses. Little is known about how this is achieved. Using C. elegans, we dissect cross-modulation between systems that monitor temperature, O and CO. CO is less aversive to animals acclimated to 15C than those grown at 22C. This difference requires the AFD neurons, which respond to both temperature and CO changes. CO evokes distinct AFD Ca responses in animals acclimated at 15C or 22C. Mutants defective in synaptic transmission can reprogram AFD CO responses according to temperature experience, suggesting reprogramming occurs cell autonomously. AFD is exquisitely sensitive to CO. Surprisingly, gradients of 0.01% CO/second evoke very different Ca responses from gradients of 0.04% CO/second. Ambient O provides further contextual modulation of CO avoidance. At 21% O tonic signalling from the O-sensing neuron URX inhibits CO avoidance. This inhibition can be graded according to O levels. In a natural wild isolate, a switch from 21% to 19% O is sufficient to convert CO from a neutral to an aversive cue. This sharp tuning is conferred partly by the neuroglobin GLB-5. The modulatory effects of O on CO avoidance involve the RIA interneurons, which are post-synaptic to URX and exhibit CO-evoked Ca responses. Ambient O and acclimation temperature act combinatorially to modulate CO responsiveness. Our work highlights the integrated architecture of homeostatic responses in C. elegans.

Rosu S et al. (2011) Science "Robust crossover assurance and regulated interhomolog access maintain meiotic crossover number."

Libuda DE, Rosu S, Villeneuve AM

[Science, 2011]

Most organisms rely on interhomolog crossovers (COs) to ensure proper meiotic chromosome segregation but make few COs per chromosome pair. By monitoring repair events at a defined double-strand break (DSB) site during Caenorhabditis elegans meiosis, we reveal mechanisms that ensure formation of the obligate CO while limiting CO number. We find that CO is the preferred DSB repair outcome in the absence of inhibitory effects of other (nascent) recombination events. Thus, a single DSB per chromosome pair is largely sufficient to ensure CO formation. Further, we show that access to the homolog as a repair template is regulated, shutting down simultaneously for both CO and noncrossover (NCO) pathways. We propose that regulation of interhomolog access limits CO number and contributes to CO interference.

Venkatachalam K et al. (2014) Cell Calcium "The role of TRPMLs in endolysosomal trafficking and function."

Zhu MX, Venkatachalam K, Wong CO

[Cell Calcium, 2014]

Members of the Transient Receptor Potential-Mucolipin (TRPML) constitute a family of evolutionarily conserved cation channels that function predominantly in endolysosomal vesicles. Whereas loss-of-function mutations in human TRPML1 were first identified as being causative for the lysosomal storage disease, Mucolipidosis type IV, most mammals also express two other TRPML isoforms called TRPML2 and TRPML3. All three mammalian TRPMLs as well as TRPML related genes in other species including Caenorhabditis elegans and Drosophila exhibit overlapping functional and biophysical properties. The functions of TRPML proteins include roles in vesicular trafficking and biogenesis, maintenance of neuronal development, function, and viability, and regulation of intracellular and organellar ionic homeostasis. Biophysically, TRPML channels are non-selective cation channels exhibiting variable permeability to a host of cations including Na(+), Ca(2+), Fe(2+), and Zn(2+), and are activated by a phosphoinositide species, PI(3,5)P2, that is mostly found in endolysosomal membranes. Here, we review the functional and biophysical properties of these enigmatic cation channels, which represent the most ancient and archetypical TRP channels.

Oti M et al. (2008) BMC Bioinformatics "Conserved co-expression for candidate disease gene prioritization."

van Reeuwijk J, Brunner HG, Oti M, Huynen MA

[BMC Bioinformatics, 2008]

ABSTRACT: BACKGROUND: Genes that are co-expressed tend to be involved in the same biological process. However, co-expression is not a very reliable predictor of functional links between genes. The evolutionary conservation of co-expression between species can be used to predict protein function more reliably than co-expression in a single species. Here we examine whether co-expression across multiple species is also a better prioritizer of disease genes than is co-expression between human genes alone. RESULTS: We use co-expression data from yeast (S. cerevisiae), nematode worm (C. elegans), fruit fly (D. melanogaster), mouse and human and find that the use of evolutionary conservation can indeed improve the predictive value of co-expression. The effect that genes causing the same disease have higher co-expression than do other genes from their associated disease loci, is significantly enhanced when co-expression data are combined across evolutionarily distant species. We also find that performance can vary significantly depending on the co-expression datasets used, and just using more data does not necessarily lead to better predictions. Instead, we find that dataset quality is more important than quantity, and using a consistent microarray platform per species leads to better performance than using more inclusive datasets pooled from various platforms. CONCLUSIONS: We find that evolutionarily conserved gene co-expression prioritizes disease candidate genes better than human gene co-expression alone, and provide the integrated data as a new resource for disease gene prioritization tools.

Libuda, Diana E. et al. (2011) International Worm Meeting "Synaptonemal Complex mediates crossover interference during meiosis."

Hayashi, Michiko, Yokoo, Rayka, Villeneuve, Anne M., Libuda, Diana E.

[International Worm Meeting, 2011]

Crossover (CO) recombination events during meiosis are critical for the formation of the chiasmata that link homologous chromosomes together and ensure their proper segregation. Despite an excess of double strand DNA breaks (DSBs) that serve as initiating events for CO formation, most organisms make few COs, and formation of a CO tends to inhibit formation of other COs nearby on the same chromosome, a process known as CO interference. C. elegans exhibits particularly robust CO interference, with only a single CO forming between each pair of homologous chromosomes, making it an ideal model for investigating how COs form and how CO interference is mediated. Here we show that the synaptonemal complex (SC), a proteinaceous structure that forms between homologous chromosomes during meiosis, regulates CO formation both by directing localization of CO-promoting proteins and by mediating CO interference along the lengths of meiotic chromosomes. Our analysis used a GFP-tagged version of COSA-1, a conserved CO-promoting factor that we identified, as a marker of CO sites. Upon onset of the late pachytene stage of meiotic prophase, GFP::COSA-1 localizes to six bright foci per nucleus, corresponding to the single CO site on each homolog pair. These foci represent the sites of eventual concentration of other conserved CO-promoting factors (MSH-5 and ZHP-3) that initially exhibit broader distribution along chromosomes. Analysis of conditions where DSBs are either limiting or in excess demonstrated that COSA-1 foci represent a robust cytological readout of the CO interference process. We exploited this property to investigate involvement of the SC central region proteins (SYPs), in formation and regulation of COs. Our data demonstrate that SYPs both: 1) dictate where CO-promoting proteins will concentrate; and 2) function in inhibiting excess CO formation. In mutants where the SC forms on only a subset of chromosomes, CO-promoting proteins localize only to those chromosomes where SYPs are present. Further, CO-promoting proteins co-localize and become sequestered with SYPs in nuclear aggregates that form when SYPs are prevented from loading onto chromosomes. Most notably, despite the fact that the SYP proteins are required to form COs, we find that partial depletion of the SYP-1 protein actually results in an increase in COSA-1 foci, implying attenuation of CO interference. These and other data implicate the SC as a key player in the robust CO interference mechanism that normally limits the number of CO events to one per homolog pair during C. elegans meiosis.

Bretscher AJ et al. (2008) Proc Natl Acad Sci U S A "A carbon dioxide avoidance behavior is integrated with responses to ambient oxygen and food in Caenorhabditis elegans."

Bretscher AJ, Busch KE, De Bono M

[Proc Natl Acad Sci U S A, 2008]

Homeostasis of internal carbon dioxide (CO(2)) and oxygen (O(2)) levels is fundamental to all animals. Here we examine the CO(2) response of the nematode Caenorhabditis elegans. This species inhabits rotting material, which typically has a broad CO(2) concentration range. We show that well fed C. elegans avoid CO(2) levels above 0.5%. Animals can respond to both absolute CO(2) concentrations and changes in CO(2) levels within seconds. Responses to CO(2) do not reflect avoidance of acid pH but appear to define a new sensory response. Sensation of CO(2) is promoted by the cGMP-gated ion channel subunits TAX-2 and TAX-4, but other pathways are also important. Robust CO(2) avoidance in well fed animals requires inhibition of the DAF-16 forkhead transcription factor by the insulin-like receptor DAF-2. Starvation, which activates DAF-16, strongly suppresses CO(2) avoidance. Exposure to hypoxia (<1% O(2)) also suppresses CO(2) avoidance via activation of the hypoxia-inducible transcription factor HIF-1. The npr-1 215V allele of the naturally polymorphic neuropeptide receptor npr-1, besides inhibiting avoidance of high ambient O(2) in feeding C. elegans, also promotes avoidance of high CO(2). C. elegans integrates competing O(2) and CO(2) sensory inputs so that one response dominates. Food and allelic variation at NPR-1 regulate which response prevails. Our results suggest that multiple sensory inputs are coordinated by C. elegans to generate different coherent foraging strategies.

Huang, Xiaobing et al. (2019) International Worm Meeting "A transgenic co-expressed Amyloid-beta and alpha-Synuclein dementia model in Caenorhabditis elegans."

Huang, Xiaobing, Leung, Ka Lai, Wang, Changliang, Chen, Liang, Shen, Linjing, Wong, Garry

[International Worm Meeting, 2019]

Purpose: Dementia with Lewy bodies (DLB) is the second most common type of progressive dementia after Alzheimer's disease dementia. Lewy bodies develop in nerve cells in brain regions where thinking, memory and movement are lost. Still, the pathology of DLB remains vague. For exploring the pathogenesis of DLB, we constructed a disease model of DLB which co-expressed Amyloid-? (A?) and ?-synuclein in pan-neurons in C. elegans. Methods: We used the locomotion, thrashing, lifespan, development and egg laying behavior assays to evaluate whether co-expressed A? and ?-synuclein would alter phenotypes in worms. Furthermore, we used confocal microscopy to analyze the neurodegeneration of worms and Thioflavin-S staining to observe the misfolded protein aggregation. Moreover, we used RNA-Seq to explore the effects of co-expressed A? and ?-synuclein in worms on transcription. Results: Our results showed that co-expressed A? and ?-synuclein severely impaired the behaviors and affected neurons in C. elegans. Worms that co-expressed A? and ?-synuclein showed uncoordinated and slower movement, shorter lifespan, less progeny and egg laying defects. Moreover, misfolded protein aggregation and damage of dopaminergic neurons were found in co-expressed A? and ?-synuclein worms, suggesting that co-expression of these 2 transgenes can cause damage to neurons beyond those observed in Alzheimer's disease or Parkinson's disease models. RNA-seq data showed that co-expression of transgenes mainly altered expression levels of genes in the TGF-beta signaling pathway, Wnt signaling pathway, ubiquitin mediated proteolysis, and protein processing pathways in endoplasmic reticulum. Conclusion: Our model might be a useful tool to discover and investigate the etiology of Dementia with Lewy bodies. Moreover, it might be an excellent model to screen drugs that can ameliorate the symptoms of dementia. Acknowledgment: This research was supported in part by the Research grant of Garry Wong MYRG2017-00123-FHS.

Mets DG et al. (2009) Cell "Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure."

Meyer BJ, Mets DG

[Cell, 2009]

Meiotic crossover (CO) recombination facilitates evolution and accurate chromosome segregation. CO distribution is tightly regulated: homolog pairs receive at least one CO, CO spacing is nonrandom, and COs occur preferentially in short genomic intervals called hotspots. We show that CO number and distribution are controlled on a chromosome-wide basis at the level of DNA double-strand break (DSB) formation by a condensin complex composed of subunits from two known condensins: the C. elegans dosage compensation complex and mitotic condensin II. Disruption of any subunit of the CO-controlling condensin dominantly changes DSB distribution, and thereby COs, and extends meiotic chromosome axes. These phenotypes are cosuppressed by disruption of a chromosome axis element. Our data implicate higher-order chromosome structure in the regulation of CO recombination, provide a model for the rapid evolution of CO hotspots, and show that reshuffling of interchangeable molecular parts can create independent machines with similar architectures but distinct biological functions.