AMPK regulates germline stem cell quiescence and integrity through an endogenous small RNA pathway

Kadekar, Pratik; Roy, Richard

doi:10.1371/journal.pbio.3000309

Cited by 29 publications

(101 citation statements)

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“…Other key signal transduction pathways critical for growth and development that are enhanced in the immature flukes include the (a) AMPK signalling pathway that regulates energy homeostasis and metabolism [ 26 , 27 ] and plays a critical role in the regulation of cell growth [ 28 ]. Recently, Kadekar and Roy [ 29 ] have shown that this pathway is also involved in regulating germline stem cells in Caenorhabditis elegans within the energy-stressed dauer stage via the small RNA pathway; (b) Hippo signalling pathway that regulates organ size through regulation of cellular proliferation and expansion of neoblasts/pluripotent cells during stages of development [ 30 – 33 ]. As the immature parasites migrate through the liver some of the reproductive organs are at an advanced stage of development, notably the testes which show a clear follicular appearance by 21 dpi in mice [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

Complementary transcriptomic and proteomic analyses reveal the cellular and molecular processes that drive growth and development of Fasciola hepatica in the host liver

et al. 2021

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Background The major pathogenesis associated with Fasciola hepatica infection results from the extensive tissue damage caused by the tunnelling and feeding activity of immature flukes during their migration, growth and development in the liver. This is compounded by the pathology caused by host innate and adaptive immune responses that struggle to simultaneously counter infection and repair tissue damage. Results Complementary transcriptomic and proteomic approaches defined the F. hepatica factors associated with their migration in the liver, and the resulting immune-pathogenesis. Immature liver-stage flukes express ~ 8000 transcripts that are enriched for transcription and translation processes reflective of intensive protein production and signal transduction pathways. Key pathways that regulate neoblast/pluripotent cells, including the PI3K-Akt signalling pathway, are particularly dominant and emphasise the importance of neoblast-like cells for the parasite’s rapid development. The liver-stage parasites display different secretome profiles, reflecting their distinct niche within the host, and supports the view that cathepsin peptidases, cathepsin peptidase inhibitors, saposins and leucine aminopeptidases play a central role in the parasite’s destructive migration, and digestion of host tissue and blood. Immature flukes are also primed for countering immune attack by secreting immunomodulating fatty acid binding proteins (FABP) and helminth defence molecules (FhHDM). Combined with published host microarray data, our results suggest that considerable immune cell infiltration and subsequent fibrosis of the liver tissue exacerbates oxidative stress within parenchyma that compels the expression of a range of antioxidant molecules within both host and parasite. Conclusions The migration of immature F. hepatica parasites within the liver is associated with an increase in protein production, expression of signalling pathways and neoblast proliferation that drive their rapid growth and development. The secretion of a defined set of molecules, particularly cathepsin L peptidases, peptidase-inhibitors, saponins, immune-regulators and antioxidants allow the parasite to negotiate the liver micro-environment, immune attack and increasing levels of oxidative stress. This data contributes to the growing F. hepatica -omics information that can be exploited to understand parasite development more fully and for the design of novel control strategies to prevent host liver tissue destruction and pathology.

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Section: Resultsmentioning

confidence: 99%

Complementary transcriptomic and proteomic analyses reveal the cellular and molecular processes that drive growth and development of Fasciola hepatica in the host liver

et al. 2021

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“…Next we used Oil Red O to examine fat storage and found that unlike other partial dauer mutants (17), the chd-7;daf-2 abnormal dauers did not exhibit fat-storage deficiencies (Supplementary Figure 1). During the dauer stage, the germ cells remains quiescent to protect their reproductive capacity (41). We observed that germ line in chd-7 mutant dauers was substantially larger than in dauers and appeared to arrest with an L3-like germ line morphology (Figure 1F).…”

Section: Chd-7 Functions In Development Of the Dauer Larvamentioning

confidence: 85%

Analysis of CHD-7 defective dauer nematodes implicates collagen misregulation in CHARGE syndrome features

Jofré

Hoffman

Cervino

et al. 2021

Preprint

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CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. However, despite the public health relevance of this disorder, relevant targets of CHD7 that relate to disease pathology are still poorly understood. Here we report that chd-7, the nematode ortholog of CHD7, is required for dauer morphogenesis, lifespan determination, and stress response. Genetic epistasis placed chd-7 in the TGF-β pathway. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the TGF-β pathway. Interestingly, DAF-12 transcriptionally upregulated chd-7, which is necessary to repress daf-9 for execution of the dauer program. Transcriptomic analysis comparing chd-7 defective and normal dauers showed enrichment of collagen genes, consistent with a conserved role for the TGF-β pathway in expression of the extracellular matrix. To validate a conserved function for chd-7 in vertebrates, we used Xenopus laevis embryos, an established model to study craniofacial development. Morpholino mediated knockdown of Chd7 led to embryonic lethality, a reduction in col2a1 mRNA levels and craniofacial defects in tadpoles. Both lethality and malformations were partially rescued in Chd7-depleted embryos by over-expression of col2a1. We suggest that pathogenic features of CHARGE syndrome caused by Chd7 mutations, such as craniofacial malformations, result from the reduction of collagen levels. These studies establish C. elegans as an amenable animal model to study the etiology of the developmental defects associated with pathogenic Chd7.

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“…Among other effects, AMPK inhibits the energy utilization hub Mechanistic Target of Rapamycin Complex-1 (mTORC1) under starvation conditions [123], placing cells in an energy conserving, nonproliferative state. The enzyme functions during development of the nematode Caenorhabditis elegans, for example, to induce quiescence in germline stem cells [124]. The quiescence-inducing role of AMPK is conserved across the eukaryotes, also appearing in plants and fungi [125,126].…”

Section: Cessation Of Movement and Quiescencementioning

confidence: 99%

Interplay of mesoscale physics and agent-like behaviors in the parallel evolution of aggregative multicellularity

Angel

Nanjundiah

Benítez

et al. 2020

EvoDevo

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Myxobacteria and dictyostelids are prokaryotic and eukaryotic multicellular lineages, respectively, that after nutrient depletion aggregate and develop into structures called fruiting bodies. The developmental processes and resulting morphological outcomes resemble one another to a remarkable extent despite their independent origins, the evolutionary distance between them and the lack of traceable homology in molecular mechanisms. We hypothesize that the morphological parallelism between the two lineages arises as the consequence of the interplay within multicellular aggregates between generic processes, physical and physicochemical processes operating similarly in living and non-living matter at the mesoscale (~10–3–10–1 m) and agent-like behaviors, unique to living systems and characteristic of the constituent cells, considered as autonomous entities acting according to internal rules in a shared environment. Here, we analyze the contributions of generic and agent-like determinants in myxobacteria and dictyostelid development and their roles in the generation of their common traits. Consequent to aggregation, collective cell–cell contacts mediate the emergence of liquid-like properties, making nascent multicellular masses subject to novel patterning and morphogenetic processes. In both lineages, this leads to behaviors such as streaming, rippling, and rounding-up, as seen in non-living fluids. Later the aggregates solidify, leading them to exhibit additional generic properties and motifs. Computational models suggest that the morphological phenotypes of the multicellular masses deviate from the predictions of generic physics due to the contribution of agent-like behaviors of cells such as directed migration, quiescence, and oscillatory signal transduction mediated by responses to external cues. These employ signaling mechanisms that reflect the evolutionary histories of the respective organisms. We propose that the similar developmental trajectories of myxobacteria and dictyostelids are more due to shared generic physical processes in coordination with analogous agent-type behaviors than to convergent evolution under parallel selection regimes. Insights from the biology of these aggregative forms may enable a unified understanding of developmental evolution, including that of animals and plants.

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AMPK regulates germline stem cell quiescence and integrity through an endogenous small RNA pathway

Cited by 29 publications

References 65 publications

Complementary transcriptomic and proteomic analyses reveal the cellular and molecular processes that drive growth and development of Fasciola hepatica in the host liver

Complementary transcriptomic and proteomic analyses reveal the cellular and molecular processes that drive growth and development of Fasciola hepatica in the host liver

Analysis of CHD-7 defective dauer nematodes implicates collagen misregulation in CHARGE syndrome features

Interplay of mesoscale physics and agent-like behaviors in the parallel evolution of aggregative multicellularity

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