Molting in<i>C. elegans</i>

Lažetić, Vladimir; Fay, David S.

doi:10.1080/21624054.2017.1330246

Cited by 92 publications

(139 citation statements)

References 144 publications

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“…The physiological relevance of our findings is further bolstered by our approach to studying NEKLs within their native context and within an intact developing organism. Moreover, given the requirement for endocytic trafficking factors in the molting process [4], as well as the strong correlation we observed between trafficking and molting defects, our findings indicate that molting defects in nekl–mlt mutants are a consequence of abnormal trafficking.…”

Section: Discussionsupporting

confidence: 67%

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Control of clathrin-mediated endocytosis by NIMA family kinases

Joseph

Wang

Lažetić

et al. 2019

Preprint

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Endocytosis, the process by which cells internalize plasma membrane and associated cargo, is regulated extensively by posttranslational modifications. Previous studies suggested the potential involvement of scores of protein kinases in endocytic control, of which only a few have been validated within their native context. Here we show that the conserved NIMA-related kinases NEKL-2/NEK8/9 and NEKL-3/NEK6/7 (the NEKLs) control clathrin-mediated endocytosis in C. elegans. Loss of NEKLs leads to clathrin mislocalization and to a dramatic reduction in clathrin mobility at the apical membrane. Strikingly, reducing the levels of active AP2, the major clathrin adapter complex, rescues nekl mutant defects, whereas increased levels of active AP2 exacerbate nekl defects. Moreover, NEKL inhibition alleviates defects associated with reduced AP2 activity, attesting to the tight link between NEKL and AP2 functions. We also show that NEKLs are required for the clustering and internalization of membrane cargo and that human NEKs rescue defects in nekl mutant worms.

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Section: Discussionsupporting

confidence: 67%

“…Endocytosis by the epidermis is also essential for the uptake of sterols from the environment, which provide building blocks for the hormonal cues that drive molting [4, 6, 9-12]. Consistent with this, worms deprived of cholesterol fail to molt [13-15].…”

Section: Introductionmentioning

confidence: 99%

Control of clathrin-mediated endocytosis by NIMA family kinases

Joseph

Wang

Lažetić

et al. 2019

Preprint

Self Cite

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“…Inhibition of molting by protease-class specific inhibitors was previously reported for A. suum L3 [46], but, with no reference to an LED-like phenotype. The tissue disintegration with LED is also distinct from well-established examples in which apolysis but no ecdysis occurs, with naturally ensheathed infective L3 of the Strongylid nematode pathogens, as one example, that infect humans and animals, or in C. elegans molting mutants [47, 48]. Further, realization of the full phenotype apparently depends on progression of L3 into a susceptible phase of the molting process.…”

Section: Discussionmentioning

confidence: 99%

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

Jasmer

Rosa

Tyagi

et al. 2019

Preprint

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Efforts to identify new drugs for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen omics databases and drug databases from which new anthelmintic compounds might be identified. Here, a novel approach focused on integrating a pan-Nematoda multi-omics data targeted to a specific nematode organ system (the intestinal tract) with evidence-based filtering and chemogenomic screening was undertaken. Based on de novo computational target prioritization of the 3,564 conserved intestine genes in A. suum, exocytosis was identified as a high priority pathway, and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. 10 of 13 inhibitors were found to cause rapid immotility in A. suum L3 larvae, and five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.Author summaryThe intestinal cells of parasitic nematodes are not known to regenerate, therefore disruption of essential processes that cause irreparable damage to intestinal cells is expected to promote worm expulsion. To facilitate improved methods of therapy we need to better understand the basic intestinal cell and tissue functions of this critical organ. To that end have undertaken a comprehensive analysis of multi-omics omics data and identify and prioritize intestinal genes/pathways with essential functions and associated drugs and established a foundational model of the STH intestinal system using the large roundworm Ascaris suum to test and validate inhibitors of these functions. We found 10 inhibitors to impacted motility, and seven of those showed severe pathology and an apparent irreparable damage to intestinal cells. Furthermore, five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Our results firmly validate the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.

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“…Hence, molting may involve processes, in particular those linked to ECM remodeling, that are executed long before the onset of lethargus. In other words, the traditional definition of molting as comprising lethargus, during which the old cuticle is detached from the epidermis and a new cuticle synthesized, and ecdysis (26), may fail to capture the full complexity and duration of this fundamental process of nematode development.…”

Section: Supplementary Textmentioning

confidence: 99%

Developmental function and state transitions of a gene expression oscillator inC. elegans

Hendriks

et al. 2019

Preprint

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Gene expression oscillators drive various repetitive biological processes. The architecture and properties of an oscillatory system can be inferred from the way it transitions, or bifurcates, between active (oscillatory) and quiescent (stable) states. Here, we have characterized the behavior of a developmental gene expression oscillator in C. elegans during naturally occurring and induced bifurcations. We observe a rigid oscillator that appears to operate near a Saddle Node on Invariant Cycle (SNIC) rather than a supercritical Hopf bifurcation, which yields specific system features. Developmental progression and the oscillation period are coupled, and the stable state of the system resembles a specific phase of the oscillator. This phase coincides with the time of transitions between different developmental stages, which are sensitive to nutrition. Hence, we speculate that the system's bifurcation may constitute a checkpoint for progression of C. elegans larval development.Gene expression oscillations occur in many other biological systems as exemplified by the circadian rhythms in metabolism and behavior (1), vertebrate somitogenesis (2), and plant lateral root branching (3), and have thus been of a long-standing interest to both experimentalists and theoreticians. A recently discovered 'C. elegans oscillator' (4, 5), i.e., a system of genes expressed in an oscillatory manner in larvae, differs from other gene expression oscillators in its unique combination of features (4, 5): an oscillation of thousands of genes is detectable at the whole animal level and occurs with large amplitudes and widely dispersed expression peak times (i.e., peak phases). It also lacks temperature-compensation such that the oscillation period increases as ambient temperature decreases. Thus, a better understanding of this oscillator can provide insights into a striking phenomenon of dynamic gene expression and may help to reveal potential common principles and idiosyncrasies of gene expression oscillators.As the properties of an oscillatory system are constrained by its architecture (6, 7), examination of oscillator behavior can be used to infer architecture and function. Relevant characteristic behaviors include a system's response to perturbations and the way it transitions, or bifurcates, between stable (quiescent) and oscillatory (active) states. However, for many biological oscillators, including those controlling somitogenesis and circadian rhythms, it has been difficult to access bifurcations.Here, we have surveyed C. elegans oscillator activity at high temporal resolution from embryogenesis to adulthood to observe naturally occurring and induced state transitions of the oscillator during development. This has enabled us to characterize the oscillator at a level where we can identify bifurcation points, and to probe the coupling of the oscillations with development.

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Molting inC. elegans

Cited by 92 publications

References 144 publications

Control of clathrin-mediated endocytosis by NIMA family kinases

Control of clathrin-mediated endocytosis by NIMA family kinases

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

Developmental function and state transitions of a gene expression oscillator inC. elegans

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