White J (2020) J Neurogenet "Of worms and men."

White J

[J Neurogenet, 2020]

Following the spectacular success of molecular genetics in deciphering the genetic code in the 1960s, several of its leading practitioners felt sufficiently emboldened to use their newly acquired skills to move on and study that most enigmatic of biological organs - the brain. Sydney Brenner's approach was to focus on Caenorhabditis elegans, a nematode that is genetically tractable, has a nervous system that generates a rich repertoire of behaviours yet is small enough to allow anatomical reconstructions with ultrastructural precision. Through force of personality and some inspired pioneering studies, Brenner managed to ignite a bonfire of enthusiasm for this organism, which has resulted in its nervous system becoming the best understood of that in any organism. Initially, many were skeptical that this rather strange structure with just a few hundred neurons would yield insights that were relevant to vertebrate nervous systems. However, fifty years on we know that the basic repertoire of molecular components of worm and human nervous systems are remarkably similar. Furthermore, worms have a similar diversity of these components rather than a primitive sub-set. It appears that the fundamental difference in a vertebrate nervous system is a huge expansion of the neural units that comprise a basic brain such as that exemplified in C. elegans.

White J (2018) Development "Obituary: John Sulston (1942-2018)."

White J

[Development, 2018]

John Sulston, a pioneer in the developmental studies of the nematode <i>C. elegans</i> who went on to spearhead the sequencing of the genome of this organism and ultimately the human genome, died on 6th March 2018, shortly after being diagnosed with stomach cancer. Here, I reflect on John's life and work, with a particular focus on his time working on the developmental genetics and lineage of <i>C. elegans</i><i>.</i>

Bird DM et al. (2005) J Nematol "A white paper on nematode comparative genomics."

Thomas WK, Mitreva M, Blaxter ML, Bird DM, McCarter JP, Sternberg PW

[J Nematol, 2005]

In response to the new opportunities for genome sequencing and comparative genomics, the Society of Nematology (SON) formed a committee to develop a white paper in support of the broad scientific needs associated with this phylum and interests of SON members. Although genome sequencing is expensive, the data generated are unique in biological systems in that genomes have the potential to be complete (every base of the genome can be accounted for), accurate (the data are digital and not subject to stochastic variation), and permanent (once obtained, the genome of a species does not need to be experimentally re-sampled). The availability of complete, accurate, and permanent genome sequences from diverse nematode species will underpin future studies into the biology and evolution of this phylum and the ecological associations (particularly parasitic) nematodes have with other organisms. We anticipate that upwards of 100 nematode genomes will be solved to varying levels of completion in the coming decade and suggest biological and practical considerations to guide the selection of the most informative taxa for sequencing.

White, Rebekah J et al. MicroPubl Biol

Oliveira Clemente, Lara, White, Rebekah J

[MicroPubl Biol, 2023]

Soil organisms are a crucial part of the terrestrial biosphere and are essential for ecosystem functioning. A major part of soil and sediment ecosystems are nematodes worms, which can be used as a bioindicator of soil status. These worms represent one of the most numerous animal phyla on earth, filling all trophic levels in the soil food web. Overall nematode abundance is related to net ecosystem productivity, and regional variations in abundance provides insight into local patterns of soil fertility and functioning.Methods for extracting nematodes from soils have been established, but these can be cumbersome, or require specialist equipment or consumables, meaning they are not always suitable for the field or remote areas. We have built on previous methods to develop a simple, more compact, and zero-waste method of extracting nematodes, using basic equipment. We demonstrate this in a small collection of soils from deforested, native forest, and reforested sites. On a larger scale, this method can be used to reflect overall ecosystem function, indicating current soil status, and future success and proliferation of reforested sites.

White J et al. (2003) Curr Biol "Cytokinesis: GAGs form the walls that separate our parts."

White J, Bednarek S

[Curr Biol, 2003]

Cytokinesis, the final step of cell division, involves the formation of membranous barriers that partition cytosol and organelles between the resultant daughter cells. Recent studies reveal a crucial role for the extracellular glycosaminoglycan chondroitin in the completion of the cleavage furrow in dividing Caenorhabditis elegans embryos.

Signe White P et al. (2021) J Evol Biol "Host genetic drift and adaptation in the evolution and maintenance of parasite resistance."

Signe White P, Arslan D, Penley M, Kim D, Morran L

[J Evol Biol, 2021]

Host-parasite interactions may often be subject to opposing evolutionary forces, which likely influence the evolutionary trajectories of both partners. Natural selection and genetic drift are two major evolutionary forces that act in host and parasite populations. Further, population size is a significant determinant of the relative strengths of these forces. In small populations, drift may undermine the persistence of beneficial alleles, potentially impeding host adaptation to parasites. Here, we investigate two questions: (1) can selection pressure for increased resistance in small, susceptible host populations overcome the effects of drift, and (2) can resistance be maintained in small host populations? To answer these questions, we experimentally evolved the hostCaenorhabditis elegansagainst its bacterial parasite,Serratia marcescens,for 13 host generations. We found that strong selection favoring increased host resistance was insufficient to counteract drift in small populations, resulting in persistently high host mortality. Additionally, in small populations of resistant hosts, we found that selection for the maintenance of resistance is not always sufficient to curb the loss of resistance. We compared these results with selection in large host populations. We found that initially resistant, large host populations were able to maintain high levels of resistance. Likewise, initially susceptible, large host populations were able to gain resistance to the parasite. These results show that strong selection pressure for survival is not always sufficient to counteract drift. In consideration ofC. elegansnatural population dynamics, we suggest that drift may often impede selection in nature.

Jin YS et al. (1994) Nature "Control of type-D GABAergic neuron differentiation by C. elegans UNC-30 homeodomain protein."

Horvitz HR, Jin YS, Hoskins R

[Nature, 1994]

The Caenorhabditis elegans gene unc-30 is required for the development and functioning of the 19 inhibitory GABAergic (gamma-aminobutyric-acid-secreting) type D motor neurons, which control locomotion(1-4). In unc-30 mutants the D neurons lack GABA(2) and have defects in axonal pathfinding and synaptic connections (J. White, personal communication). We report here that unc-30 encodes a homeodomain protein that is present in the nuclei of the D neurons at high levels in young larvae, in which the motor circuitry is formed, and at low levels in older animals. The UNC-30 protein is also present in six non-GABAergic neurons and is absent from the seven non-D-type GABAergic neurons. Ectopic expression of unc-30 induced GABA expression in cells that are normally not GABAergic. We propose that unc-30 functions as a transcriptional regulator within the type D neurons to control their terminal differentiation and that unc-30 is sufficient in some but not all cell types to induce GABA expression.

White H et al. (2023) J Vis Exp "Automated Multimodal Stimulation and Simultaneous Neuronal Recording from Multiple Small Organisms."

White H, Busby M, Albrecht DR, Gorski V, Kamara V

[J Vis Exp, 2023]

Fluorescent genetically encoded calcium indicators have contributed greatly to our understanding of neural dynamics from the level of individual neurons to entire brain circuits. However, neural responses may vary due to prior experience, internal states, or stochastic factors, thus generating the need for methods that can assess neural function across many individuals at once. Whereas most recording techniques examine a single animal at a time, we describe the use of wide-field microscopy to scale up neuronal recordings to dozens of Caenorhabditis elegans or other sub-millimeter-scale organisms at once. Open-source hardware and software allow great flexibility in programming fully automated experiments that control the intensity and timing of various stimulus types, including chemical, optical, mechanical, thermal, and electromagnetic stimuli. In particular, microfluidic flow devices provide precise, repeatable, and quantitative control of chemosensory stimuli with sub-second time resolution. The NeuroTracker semi-automated data analysis pipeline then extracts individual and population-wide neural responses to uncover functional changes in neural excitability and dynamics. This paper presents examples of measuring neuronal adaptation, temporal inhibition, and stimulus crosstalk. These techniques increase the precision and repeatability of stimulation, allow the exploration of population variability, and are generalizable to other dynamic fluorescent signals in small biosystems from cells and organoids to whole organisms and plants.

White GE et al. (2003) J Exp Biol "The pathway of myofibrillogenesis determines the interrelationship between myosin and paramyosin synthesis in Caenorhabditis elegans."

White GE, Schachat F, Petry CM

[J Exp Biol, 2003]

Examination of null mutants in myosin B and paramyosin yields insights into the complex mechanisms that regulate expression of the three major components of Caenorhabditis elegans body-wall muscle thick filaments myosin A, myosin B and paramyosin. In the absence of myosin B, paramyosin accumulation is reduced, although neither its synthesis nor that of myosin A is affected. This implies that the interaction of myosin B with paramyosin inhibits paramyosin degradation. By contrast, the absence of paramyosin results in reduced synthesis and accumulation of myosin B but has no effect on myosin A synthesis. The non-reciprocal effects of the null mutants on turnover and synthesis are best understood as an epigenetic phenomenon that reflects the pathway of thick filament assembly. The synthesis of myosin A and paramyosin, which are involved in the initial steps of thick filament formation, is independent of myosin B; however, a properly assembled paramyosin-containing thick filament core is essential for efficient synthesis of myosin B.

White AR et al. (2002) J Neurosci "Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer's disease amyloid precursor protein."

Cappai R, Beyreuther K, Galatis D, Pipkorn R, White AR, McKinstry WJ, Multhaup G, Masters CL, Parker MW

[J Neurosci, 2002]

The amyloid precursor protein (APP) of Alzheimer''s disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is similar among the APP family paralogs [amyloid precursor-like proteins (APLP1 and APLP2)] and its orthologs (including Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans), suggesting an overall conservation in its function or activity. The APP CuBD is involved in modulating Cu homeostasis and amyloid beta peptide production. In this paper, we demonstrate for the first time that Cu-metallated full-length APP ectodomain induces neuronal cell death in vitro. APP Cu neurotoxicity can be induced directly or potentiated through Cu(I)-mediated oxidation of low-density lipoprotein, a finding that may have important implications for the role of lipoproteins and membrane cholesterol composition in AD. Cu toxicity induced by human APP, Xenopus APP, and APLP2 CuBDs is dependent on conservation of histidine residues at positions corresponding to 147 and 151 of human APP. Intriguingly, APP orthologs with different amino acid residues at these positions had dramatically altered Cu phenotypes. The corresponding C. elegans APL-1 CuBD, which has tyrosine and lysine residues at positions 147 and 151, respectively, strongly protected against Cu-mediated lipid peroxidation and neurotoxicity in vitro. Replacement of histidines 147 and 151 with tyrosine and lysine residues conferred this neuroprotective Cu phenotype to human APP, APLP2, and Xenopus APP CuBD peptides. Moreover, we show that the toxic and protective CuBD phenotypes are associated with differences in Cu binding and reduction. These studies identify a significant evolutionary change in the function of the CuBD in modulating Cu metabolism. Our findings also suggest that targeting of inhibitors to histidine residues at positions 147 and 151 of APP could significantly alter the oxidative potential of APP.