Ranner, T. et al. (2017) International Worm Meeting "A new biomechanical model links material properties with locomotion behaviors and predicts that gait modulation is a form of speed optimisation in C. elegans."

Cohen, N., Ranner, T.

[International Worm Meeting, 2017]

An organism's ability to move freely is a fundamental behaviour across the animal kingdom. We present a biomechanical model of C. elegans locomotion together with a novel computational approach. We model the body as a flexible elastic shell, subject to muscle forcing along the body walls of the body. All parameters are grounded in behavioral, anatomical or physiological data. Our numerical approach allows us to solve for arbitrary body shapes. Our model replicates behaviours across a wide range of environments. We use it to study forward locomotion undulation gaits, linking between the animal's material properties and its performance across a range of viscoelastic environments. The model makes strong predictions on the viable range of the worm's Young's modulus and suggests that animals can control speed via the known mechanism of gait modulation that is observed across different media.

Denham, J. et al. (2017) International Worm Meeting "An integrated neuro-mechanical model of C. elegans forward locomotion."

Ranner, T., Denham, J., Cohen, N.

[International Worm Meeting, 2017]

Behavioural responses in C. elegans can be observed through changes in locomotive patterns. It is therefore important to consider the role of the physics in computational models of the neural circuit for motor behaviours. We present a dynamical systems model of C. elegans forward locomotion in which the neural circuit is divided into a series of repeating identical units, coupled via posterior stretch receptor feedback. Each unit includes cholinergic, bistable B-type motor neurons (modelled after bistable RMD neurons, Mellem et al. 2008, Boyle et al. 2012), implicit GABAergic D-type motor neurons (Boyle et al. 2012) and nonlinear viscoelastic muscle forcing along the body (Boyle et. al. 2012). The neural model incorporates proprioceptive feedback as the mechanism for producing sustained oscillations. Integrating the neural model with a recent continuum mechanical body model (Cohen and Ranner 2017) provides this feedback and is also the method for incorporating environmental drag from the surrounding fluid, closing the neuronal-environmental loop. Biophysically realistic parameters are used to obtain sustained travelling waves in muscle activation which respond to changes in environmental viscoelasticity. To explore the pattern generation mechanism, we present results from bifurcation analysis performed in the isolated neural framework and in the fully integrated neuro-mechanical model. We show how these results are modulated by changes in the external drag and internal material properties of the passive and active body. References [1] Boyle JH, Berri S, Cohen N: Gait modulation in c. elegans: an integrated neuro-mechanical model. Frontiers in computational neuroscience 2012, 6:10. [2] Mellem JE, Brockie PJ, Madsen DM, Maricq AV: Action potentials contribute to neuronal signaling in C. elegans, Nature Neuroscience 2008, 11:865-867 [3] Cohen N, Ranner T: A new computational method for a model of C. elegans biomechanics: Insights into elasticity and locomotion performance, arXiv:1702.04988, 20

Denham, J.E. et al. (2019) International Worm Meeting "Signatures of central and peripheral control in an integrated neuromechanical model of C. elegans locomotion."

Denham, J.E., Cohen, N., Ranner, T.

[International Worm Meeting, 2019]

Animal neuromechanics describes the coordinated self-propelled movement of a body, subject to the combined effects of internal neural control and mechanical forces. Here we use a computational model to disentangle manifestations of neural and mechanical modulation of undulatory locomotion of C. elegans, with a focus on proprioceptively driven and central pattern generated neural control. We reveal a fundamental relationship linking body elasticity, internal viscosity and environmental drag in determining the dynamics of the body and demonstrate the manifestation of this relationship in the context of proprioceptively driven control. By modulating characteristics unique to proprioceptive neurons, we predict the signatures of internal gait modulation that contrast with the known signatures of externally or biomechanically modulated gait. We analyse the common and contrasting signatures of different models of proprioceptive and central pattern generated control. First, we show that, unlike central pattern generated control, proprioceptive feedback can suppress neuromechanical phase lags during undulatory locomotion. Second, we explore manipulations of the neural and mechanical systems and relate the results with recently published experimental findings.

Denham JE et al. (2018) Philos Trans R Soc Lond B Biol Sci "Signatures of proprioceptive control in Caenorhabditis elegans locomotion."

Cohen N, Denham JE, Ranner T

[Philos Trans R Soc Lond B Biol Sci, 2018]

Animal neuromechanics describes the coordinated self-propelled movement of a body, subject to the combined effects of internal neural control and mechanical forces. Here we use a computational model to identify effects of neural and mechanical modulation on undulatory forward locomotion of <i>Caenorhabditis elegans</i>, with a focus on proprioceptively driven neural control. We reveal a fundamental relationship between body elasticity and environmental drag in determining the dynamics of the body and demonstrate the manifestation of this relationship in the context of proprioceptively driven control. By considering characteristics unique to proprioceptive neurons, we predict the signatures of internal gait modulation that contrast with the known signatures of externally or biomechanically modulated gait. We further show that proprioceptive feedback can suppress neuromechanical phase lags during undulatory locomotion, contrasting with well studied advancing phase lags that have long been a signature of centrally generated, feed-forward control.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling <i>C. elegans</i> at cellular resolution'.

Holbrook, R.I. et al. (2017) International Worm Meeting "Novel 3D locomotion, body postures and exploration behaviour in Caenorhabditis elegans."

Holbrook, R.I., Salfelder, F., Ranner, T., Cohen, N.

[International Worm Meeting, 2017]

How animals move through their natural habitats is fundamental to understanding their biology. We possess considerable knowledge of Caenorhabditis elegans locomotion and movement behaviour from extensive investigations of these animals living on the 2D surface of an agar plate. However, C. elegans in the wild live in the complex-structured 3D environment of decaying vegetation, and we have very limited information about how C. elegans behaves in their natural habitats. This raises concerns that C. elegans locomotion data collected in 2D may be incomplete and unrepresentative, severely limiting our models and predictions about their neural control, biomechanics and movement. One reason for the gap in our knowledge is the difficulty in recording accurate 3D movements of animals at the scale of C. elegans (~1 mm) with high spatial and temporal resolution. At the macro scale, conventional 3D imaging relies on multiple camera views with overlapping focus regions, but lenses do not have sufficient magnification to image at the C. elegans scale. Conventional microscopes have a very narrow depth of focus so cannot be used in a multiple camera system. Instead, they have to employ Z-stacking to image static bodies in 3D, making them unsuitable for imaging a freely moving body in real-time. To overcome these obstacles, we built a 3D imaging system using three telecentric lenses each with a 7- 21 mm depth of focus (depending on the magnification) attached to three 4.2 megapixel cameras. This system allows us to image the worm moving freely through up to 9.2 cm3. This volume is calibrated using photogrammetry to solve for the lens distortion and camera geometry. A novel image analysis algorithm produces accurate reconstructions of the 3D posture, in the form of a smooth midline, and location of the worm within the volume. We recorded individual worms moving freely through a range of viscoelastic fluids corresponding to different concentrations of gelatine in M9 buffer solution. All recordings were between 25 and 45 Hz. Across a wide range of viscoelasticities, we found that the body postures of the worm are more commonly 3D than 2D. Specifically, we report novel 3D body postures exhibited by C. elegans, including a helicoid locomotion gait and a "lasso" turning posture. Furthermore, the trajectories of the worms are more commonly 3D than 2D. These kinematic and performance data inform a new integrated and 3D neuromechanical locomotion model.

Samuel ADT et al. (2003) J Neurosci "Synaptic activity of the AFD neuron in Caenorhabditis elegans correlates with thermotactic memory."

Murthy VN, Samuel ADT, Silva RA

[J Neurosci, 2003]

Thermotactic behavior in Caenorhabditis elegans is sensitive to both a worm's ambient temperature (T-amb) and its memory of the temperature of its cultivation (T-cult). The AFD neuron is part of a neural circuit that underlies thermotactic behavior. By monitoring the fluorescence of pH-sensitive green fluorescent protein localized to synaptic vesicles, we measured the rate of the synaptic release of AFD in worms cultivated at temperatures between 15 and 25degreesC, and subjected to fixed, ambient temperatures in the same range. We found that the rate of AFD synaptic release is high if either T-amb > T-cult or T-amb > T-cult, but AFD synaptic release is low if T-amb congruent to T-cult. This suggests that AFD encodes a direct comparison between T-amb and T-cult.

Yuval, O. et al. (2019) International Worm Meeting "Characterization of C. elegans motor behaviour in 3D environment?s."

Ranner, T., Yuval, O., Salfelder, F., Cohen, N.

[International Worm Meeting, 2019]

In its natural habitat, C. elegans maneuvers through 3D environments with complex physical and chemical properties. However, to date, the worm's locomotion has been studied almost exclusively in quasi-planar settings, such as on an agar surface. Observing how the worm moves in more natural environments may unravel new behaviors that may allow us to push forward our understanding of their underlying neural and biomechanical control mechanisms. Understanding the interplay between the biomechanics and neural control in C. elegans requires a characterization of the anatomy, mechanics and neurobiology. We adopted an integrated approach, combining 3D imaging of freely-moving animals with quantitative behavioral characterization and neural and biomechanical modeling. Using an experimentally-grounded computation model, we capture observed behaviors with a view to making testable predictions. We recorded freely-moving worms in different gelatin concentrations in M9 buffer. Our 3D imaging system consists of three telecentric lenses attached to 4.2MP cameras. Worms move freely through a large cube with 2-21mm depth of focus and recorded at 25-45 Hz. The imaged volume is calibrated using photogrammetry to solve for the lens distortion and camera geometry. A novel image analysis algorithm produces accurate reconstructions of the 3D posture, and location of the worm within the volume. We use a worm-reference coordinate system to find a low-dimensional representation of non-planar body postures to quantify their evolution continuously over time. Across a wide range of gelatin concentrations, we observe transitions between planar and non-planar postures and link postural dynamics to worm speed, trajectory and possible behavioral strategies. We have developed a 3D biomechanical model that integrates neural and mechanical control to generate locomotion dynamics in different environments. In this model, the body of the worm is modeled as a continuum viscoelastic shell with internal pressure, subject to the balance of internal (e.g. muscle activation) and external (environmental) forces, which we solve for the midline of the worm. The muscles, which are attached to the cuticle, provide the link between neural control and body deformation that can give rise to bending in both the dorso-ventral and left-right directions, captured in our anatomically grounded coordinate system. The model was parameterized and validated using 2D scenarios, before adding three dimensional components.

Bommireddy R et al. (2007) Trends Mol Med "TGFbeta1 and Treg cells: alliance for tolerance."

Bommireddy R, Doetschman T

[Trends Mol Med, 2007]

Transforming growth factor beta1 (TGFbeta1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T(reg))-cell and effector-cell function and tumorigenesis. Defects in TGFbeta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFbeta1 prevents abnormal T-cell activation through the modulation of Ca(2+)-calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T(reg) cells, its effects are mediated, at least in part, through SMAD signaling. TGFbeta1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T(h) IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFbeta1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.

Agulnik SI et al. (1995) Genomics "Conservation of the T-box gene family from Mus musculus to Caenorhabditis elegans."

Bollag RJ, Silver LM, Agulnik SI

[Genomics, 1995]

Recently, a novel family of genes with a region of homology to the mouse T locus, which is known to play a crucial, and conserved, role in vertebrate development, has been discovered. The region of homology has been named the T-box. The T-box domain of the prototypical T locus product is associated with sequence-specific DNA binding activity. In this report, we have characterized four members of the T-box gene family from the nematode Caenorhabditis elegans. All lie in close proximity to each other in the middle of chromosome III. Homology analysis among all completely sequenced T-box products indicates a larger size for the conserved T-box domain (166 to 203 residues) than previously reported. Phylogenetic analysis suggests that one C. elegans T-box gene may be a direct ortholog of the mouse Tbx2 and Drosophila omb genes. The accumulated data demonstrate the ancient nature of the T-box gene family and suggest the existence of at least three separate T-box-containing genes in a common early metazoan ancestor to nematodes and vertebrates.

Ju T et al. (2006) Glycobiology "Identification of core 1 O-glycan T-synthase from Caenorhabditis elegans."

Ju T, Zheng Q, Cummings RD

[Glycobiology, 2006]

The common O-glycan core structure in animal glycoproteins is the core 1 disaccharide Galbeta1-3GalNAcalpha1-Ser/Thr, which is generated by addition of Gal to GalNAcalpha1-Ser/Thr by core 1 UDP-Gal:GalNAcalpha1-Ser/Thr beta1,3-galactosyltransferase (core 1 beta3-Gal-T or T-synthase, EC2.4.1.122)(2). Although O-glycans play important roles in vertebrates, much remains to be learned from model organisms such as the free-living nematode Caenorhabditis elegans, which offer many advantages in exploring O-glycan structure/function. Here we report the cloning and enzymatic characterization of T-synthase from C. elegans (Ce-T-synthase). A putative C. elegans gene for T-synthase, C38H2.2, was identified in GenBank by a BlastP search using the human T-synthase protein sequence. The full-length cDNA for Ce-T-synthase, which was generated by PCR using a C. elegans cDNA library as the template, contains 1,170 bp including the stop TAA. The cDNA encodes a protein of 389 amino acids with typical type-II membrane topology and a remarkable 42.7% identity to the human T-synthase. Ce-T-synthase has 7 Cys residues in the lumenal domain including 6 conserved Cys residues in all of the orthologs. The Ce-T-synthase has 4 potential N-glycosylation sequons, whereas the mammalian orthologs lack N-glycosylation sequons. Only one gene for Ce-T-synthase was identified in the genome-wide search and it contains 8 exons. Promoter analysis of the Ce-T-synthase using green fluorescent protein constructs show that the gene is expressed at all developmental stages and appears to be in all cells. Unexpectedly, only minimal activity was recovered in the recombinant, soluble Ce-T-synthase secreted from a wide variety of mammalian cell lines, whereas robust enzyme activity was recovered in the soluble Ce-T-synthase expressed in Hi-5 insect cells. Vertebrate T-synthase requires the molecular chaperone Cosmc, but our results show that Ce-T-synthase does not require Cosmc, and might require invertebrate-specific factors for formation of the optimally active enzyme. These results show that the Ce-T-synthase is a functional ortholog to the human T-synthase in generating core 1 O-glycans and opens new avenues to explore O-glycan function in this model organism.