scholarly journals Loss of the seipin gene perturbs eggshell formation in Caenorhabditiselegans

Development ◽  
2020 ◽  
Vol 147 (20) ◽  
pp. dev192997 ◽  
Author(s):  
Xiaofei Bai ◽  
Leng-Jie Huang ◽  
Sheng-Wen Chen ◽  
Benjamin Nebenfuehr ◽  
Brian Wysolmerski ◽  
...  
Keyword(s):  
Dietary Supplementation ◽  
Embryonic Lethality ◽  
Human Diseases ◽  
Lipid Homeostasis ◽  
Permeability Barrier ◽  
Deletion Mutants ◽  
Pufa Supplementation ◽  
C Elegans ◽  
Innermost Layer ◽  
Fatty Acid Pool

ABSTRACTSeipin, an evolutionary conserved protein, plays pivotal roles during lipid droplet (LD) biogenesis and is associated with various human diseases with unclear mechanisms. Here, we analyzed Caenorhabditis elegans mutants deleted of the sole SEIPIN gene, seip-1. Homozygous seip-1 mutants displayed penetrant embryonic lethality, which is caused by the disruption of the lipid-rich permeability barrier, the innermost layer of the C. elegans embryonic eggshell. In C. elegans oocytes and embryos, SEIP-1 is associated with LDs and is crucial for controlling LD size and lipid homeostasis. The seip-1 deletion mutants reduced the ratio of polyunsaturated fatty acids (PUFAs) in their embryonic fatty acid pool. Interestingly, dietary supplementation of selected n-6 PUFAs rescued the embryonic lethality and defective permeability barrier. Accordingly, we propose that SEIP-1 may maternally regulate LD biogenesis and lipid homeostasis to orchestrate the formation of the permeability barrier for eggshell synthesis during embryogenesis. A lipodystrophy allele of seip-1 resulted in embryonic lethality as well and could be rescued by PUFA supplementation. These experiments support a great potential for using C. elegans to model SEIPIN-associated human diseases.

scholarly journals Dietary supplementation with PUFAs rescues the eggshell defects caused by seipin mutations in C. elegans

2020 ◽  
Author(s):  
Xiaofei Bai ◽  
Leng-Jie Huang ◽  
Sheng-Wen Chen ◽  
Ben Nebenfuehr ◽  
Brian Wysolmerski ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Fatty Acid Biosynthesis ◽  
Gene Expression Pattern ◽  
Dietary Supplementation ◽  
Embryonic Lethality ◽  
Permeability Barrier ◽  
Deletion Mutants ◽  
Functional Roles ◽  
C Elegans ◽  
Barrier Formation

AbstractSEIPIN, an ER membrane protein, plays critical roles in lipid droplet (LD) formation and lipid storage. Dysfunction of SEIPIN causes a variety of human diseases, including lipodystrophy, neuropathies, and male and female infertility. However, the cellular and molecular mechanisms of SEIPIN in causing these diseases are poorly understood. To address such mechanisms, we investigated the functional roles of R01B10.6 (seip-1), the sole SEIPIN1 ortholog in C. elegans, using CRISPR/Cas9 gene editing, and transcriptional assays. SEIP-1::mScarlet is widely expressed throughout development in C. elegans. Three full gene deletion mutants, generated by CRISPR/Cas9, displayed penetrant embryonic lethality. EM imaging and the visualization of reporter genes revealed that the lipid-rich permeability barrier, the innermost layer of the C. elegans embryonic eggshell, was defective or missing. Intriguingly, depletion of SEIP-1 revealed a perturbed gene expression pattern for fatty acid biosynthesis enzymes, in agreement with the disrupted permeability barrier formation phenotype of the embryos. Lastly, dietary supplementation of PUFAs rescued the embryonic lethality and defective permeability barrier in the deletion mutants. In sum, our study suggests that SEIP-1 may maternally regulate LD biogenesis and maintain lipid homeostasis to orchestrate the formation of the lipid-rich permeability barrier, which is crucial for eggshell formation and embryogenesis.

scholarly journals Specific collagens maintain the cuticle permeability barrier in Caenorhabditis elegans

Genetics ◽  
2021 ◽  
Author(s):  
Anjali Sandhu ◽  
Divakar Badal ◽  
Riya Sheokand ◽  
Shalini Tyagi ◽  
Varsha Singh
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Barrier Function ◽  
Permeability Barrier ◽  
Nematode Caenorhabditis Elegans ◽  
Zinc Finger Transcription Factor ◽  
Outermost Layer ◽  
C Elegans ◽  
Receptor Mutant ◽  
Antioxidant Machinery

Abstract Collagen enriched cuticle forms the outermost layer of skin in nematode Caenorhabditis elegans. The nematode’s genome encodes 177 collagens, but little is known about their role in maintaining the structure or barrier function of the cuticle. In this study, we found six permeability determining (PD) collagens. Loss of any of these PD collagens- DPY-2, DPY-3, DPY-7, DPY-8, DPY-9, and DPY-10- led to enhanced susceptibility of nematodes to paraquat (PQ) and antihelminthic drugs levamisole and ivermectin. Upon exposure to paraquat, PD collagen mutants accumulated more PQ and incurred more damage and death despite the robust activation of antioxidant machinery. We find that BLMP-1, a zinc finger transcription factor, maintains the barrier function of the cuticle by regulating the expression of PD collagens. We show that the permeability barrier maintained by PD collagens acts in parallel to FOXO transcription factor DAF-16 to enhance survival of insulin-like receptor mutant, daf-2. In all, this study shows that PD collagens regulate cuticle permeability by maintaining the structure of C. elegans cuticle and thus provide protection against exogenous toxins.

scholarly journals PUFA Supplementation and Heart Failure: Effects on Fibrosis and Cardiac Remodeling

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2965
Author(s):  
Francesca Oppedisano ◽  
Rocco Mollace ◽  
Annamaria Tavernese ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Dietary Supplementation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Related Factor ◽  
Ventricular Ejection Fraction ◽  
Pufa Supplementation ◽  
Positive Effects ◽  
Mitral Annulus Velocity

Heart failure (HF) characterized by cardiac remodeling is a condition in which inflammation and fibrosis play a key role. Dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) seems to produce good results. In fact, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory and antioxidant properties and different cardioprotective mechanisms. In particular, following their interaction with the nuclear factor erythropoietin 2 related factor 2 (NRF2), the free fatty acid receptor 4 (Ffar4) receptor, or the G-protein coupled receptor 120 (GPR120) fibroblast receptors, they inhibit cardiac fibrosis and protect the heart from HF onset. Furthermore, n-3 PUFAs increase the left ventricular ejection fraction (LVEF), reduce global longitudinal deformation, E/e ratio (early ventricular filling and early mitral annulus velocity), soluble interleukin-1 receptor-like 1 (sST2) and high-sensitive C Reactive protein (hsCRP) levels, and increase flow-mediated dilation. Moreover, lower levels of brain natriuretic peptide (BNP) and serum norepinephrine (sNE) are reported and have a positive effect on cardiac hemodynamics. In addition, they reduce cardiac remodeling and inflammation by protecting patients from HF onset after myocardial infarction (MI). The positive effects of PUFA supplementation are associated with treatment duration and a daily dosage of 1–2 g. Therefore, both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) define dietary supplementation with n-3 PUFAs as an effective therapy for reducing the risk of hospitalization and death in HF patients. In this review, we seek to highlight the most recent studies related to the effect of PUFA supplementation in HF. For that purpose, a PubMed literature survey was conducted with a focus on various in vitro and in vivo studies and clinical trials from 2015 to 2021.

scholarly journals Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection

2019 ◽  
Vol 116 (44) ◽  
pp. 22322-22330 ◽  
Author(s):  
James D. Nhan ◽  
Christian D. Turner ◽  
Sarah M. Anderson ◽  
Chia-An Yen ◽  
Hans M. Dalton ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Mapk Signaling ◽  
Host Responses ◽  
Lipid Homeostasis ◽  
Epigenetic Landscape ◽  
C Elegans ◽  
Metabolic Outcomes ◽  
Cellular Defenses ◽  
Pathogen Response ◽  
Lipid Stores

Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from pathogen response genes while restoring somatic lipid distribution. In addition, activating p38/MAPK signaling in the absence of pathogens, is sufficient to drive SKN-1–dependent loss of somatic fat. These data define a SKN-1– and p38-dependent axis for coordinating pathogen responses, lipid homeostasis, and survival and identify transcriptional redirection, rather than inactivation, as a mechanism for counteracting the pleiotropic consequences of aberrant transcriptional activity.

Embryonic lethality caused by mutations in basement membrane collagen of C. elegans

Nature ◽  
1991 ◽  
Vol 349 (6311) ◽  
pp. 707-709 ◽  
Author(s):  
Xiaodu Guo ◽  
Jeffrey J. Johnson ◽  
James M. Kramer
Keyword(s):  
Basement Membrane ◽  
Embryonic Lethality ◽  
C Elegans ◽  
Basement Membrane Collagen ◽  
Membrane Collagen

scholarly journals DNA Methylation on N6-Adenine Regulates the Hyphal Development during Dimorphism in the Early-Diverging Fungus Mucor lusitanicus

2021 ◽  
Vol 7 (9) ◽  
pp. 738
Author(s):  
Macario Osorio-Concepción ◽  
Carlos Lax ◽  
Eusebio Navarro ◽  
Francisco E. Nicolás ◽  
Victoriano Garre
Keyword(s):  
Wild Type Strain ◽  
Pathogenic Fungi ◽  
Infection Process ◽  
Deletion Mutants ◽  
Polar Growth ◽  
Wild Type ◽  
C Elegans ◽  
Double Deletion ◽  
Multiple Processes ◽  
Causative Agents

The epigenetic modifications control the pathogenicity of human pathogenic fungi, which have been poorly studied in Mucorales, causative agents of mucormycosis. This order belongs to a group referred to as early-diverging fungi that are characterized by high levels of N6-methyldeoxy adenine (6mA) in their genome with dense 6mA clusters associated with actively expressed genes. AlkB enzymes can act as demethylases of 6mA in DNA, with the most remarkable eukaryotic examples being mammalian ALKBH1 and Caenorhabditis elegans NMAD-1. The Mucor lusitanicus (formerly M. circinelloides f. lusitanicus) genome contains one gene, dmt1, and two genes, dmt2 and dmt3, encoding proteins similar to C. elegans NMAD-1 and ALKBH1, respectively. The function of these three genes was analyzed by the generation of single and double deletion mutants for each gene. Multiple processes were studied in the mutants, but defects were only found in single and double deletion mutants for dmt1. In contrast to the wild-type strain, dmt1 mutants showed an increase in 6mA levels during the dimorphic transition, suggesting that 6mA is associated with dimorphism in M. lusitanicus. Furthermore, the spores of dmt1 mutants challenged with macrophages underwent a reduction in polar growth, suggesting that 6mA also has a role during the spore–macrophage interaction that could be important in the infection process.

scholarly journals Mitotic chromosome condensation requires phosphorylation of the centromeric protein KNL-2 in C. elegans

2021 ◽  
Author(s):  
Joanna M Wenda ◽  
Reinier F Prosée ◽  
Caroline Gabus ◽  
Florian A Steiner
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Chromosome ◽  
Chromosome Condensation ◽  
Embryonic Lethality ◽  
Phosphorylation Sites ◽  
C Elegans ◽  
Microtubule Attachment ◽  
Centromeric Protein ◽  
Mitotic Chromosome Condensation

Centromeres are chromosomal regions that serve as sites for kinetochore formation and microtubule attachment, processes that are essential for chromosome segregation during mitosis. Centromeres are almost universally defined by the histone variant CENP-A. In the holocentric nematode C. elegans, CENP-A deposition depends on the loading factor KNL-2. Depletion of either CENP-A or KNL-2 results in defects in centromere maintenance, chromosome condensation and kinetochore formation, leading to chromosome segregation failure. Here, we show that KNL-2 is phosphorylated by CDK-1, and that mutation of three C-terminal phosphorylation sites causes chromosome segregation defects and an increase in embryonic lethality. In strains expressing phosphodeficient KNL-2, CENP-A and kinetochore proteins are properly localised, indicating that the role of KNL-2 in centromere maintenance is not affected. Instead, the mutant embryos exhibit reduced mitotic levels of condensin II on chromosomes and significant chromosome condensation impairment. Our findings separate the functions of KNL-2 in CENP-A loading and chromosome condensation and demonstrate that KNL-2 phosphorylation regulates the cooperation between centromeric regions and the condensation machinery in C. elegans.

scholarly journals DNA Methylation on N6-Adenine Regulates the Hyphal Development During Dimorphism in the Early-Diverging Fungus Mucor lusitanicus

2021 ◽  
Author(s):  
Macario Osorio-Concepción ◽  
Carlos Lax ◽  
Eusebio Navarro ◽  
Francisco E. Nicolás ◽  
Victoriano Garre
Keyword(s):  
Wild Type Strain ◽  
Pathogenic Fungi ◽  
Infection Process ◽  
Deletion Mutants ◽  
Polar Growth ◽  
Wild Type ◽  
C Elegans ◽  
Double Deletion ◽  
Multiple Processes ◽  
Causative Agents

The epigenetic modifications control the pathogenicity of human pathogenic fungi, which have been poorly studied in Mucorales; causative agents of mucormycosis. This order belongs to a group referred to as early-diverging fungi that are characterized by high levels of N6-methyldeoxyadenine (6mA) in their genome with dense 6mA clusters associated with actively expressed genes. AlkB enzymes can act as demethylases of 6mA in DNA, with the most remarkable eukaryotic examples being mammalian ALKBH1 and Caenorhabditis elegans NMAD-1. Mucor lusitanicus (formerly M. circinelloides f. lusitanicus) genome contains one gene, dmt1, and two genes, dmt2 and dmt3, encoding proteins homologs to C. elegans NMAD-1 and ALKBH1, respectively. The function of the three genes was analyzed by the generation of single and double deletion mutants for each gene. Multiple processes were studied in the mutants, but defects were only found in single and double deletion mutants for dmt1. In contrast to the wild-type strain, dmt1 mutants showed an increase of 6mA levels during the dimorphic transition, suggesting that 6mA regulates dimorphism in M. lusitanicus. Furthermore, the spores of dmt1 mutants challenged with macrophages underwent a reduction of polar growth, suggesting that 6mA also has a role during the spore-macrophage interaction that could be important in the infection process.

scholarly journals Oleic Acid Protects Caenorhabditis Mothers From Mating-Induced Death and the Cost of Reproduction

2021 ◽  
Vol 9 ◽  
Author(s):  
Leo S. Choi ◽  
Cheng Shi ◽  
Jasmine Ashraf ◽  
Salman Sohrabi ◽  
Coleen T. Murphy
Keyword(s):  
Oleic Acid ◽  
Fat Metabolism ◽  
Dietary Supplementation ◽  
Cost Of Reproduction ◽  
Costs Of Reproduction ◽  
Short Term ◽  
C Elegans ◽  
Δ9 Desaturase ◽  
The Cost

Reproduction comes at a cost, including accelerated death. Previous studies of the interconnections between reproduction, lifespan, and fat metabolism in C. elegans were predominantly performed in low-reproduction conditions. To understand how increased reproduction affects lifespan and fat metabolism, we examined mated worms; we find that a Δ9 desaturase, FAT-7, is significantly up-regulated. Dietary supplementation of oleic acid (OA), the immediate downstream product of FAT-7 activity, restores fat storage and completely rescues mating-induced death, while other fatty acids cannot. OA-mediated lifespan restoration is also observed in C. elegans mutants suffering increased death from short-term mating, and in mated C. remanei females, indicating a conserved role of oleic acid in post-mating lifespan regulation. Our results suggest that increased reproduction can be uncoupled from the costs of reproduction from somatic longevity regulation if provided with the limiting lipid, oleic acid.

scholarly journals Regulated lipid synthesis and LEM2/CHMP7 jointly control nuclear envelope closure

2020 ◽  
Vol 219 (5) ◽  
Author(s):  
Lauren Penfield ◽  
Raakhee Shankar ◽  
Erik Szentgyörgyi ◽  
Alyssa Laffitte ◽  
Michael Sean Mauro ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
De Novo ◽  
Lipid Synthesis ◽  
Meiotic Spindle ◽  
Permeability Barrier ◽  
3D Analysis ◽  
C Elegans ◽  
Cytoplasmic Membranes ◽  
Spindle Microtubules ◽  
Glycerolipid Synthesis

The nuclear permeability barrier depends on closure of nuclear envelope (NE) holes. Here, we investigate closure of the NE opening surrounding the meiotic spindle in C. elegans oocytes. ESCRT-III components accumulate at the opening but are not required for nuclear closure on their own. 3D analysis revealed cytoplasmic membranes directly adjacent to NE holes containing meiotic spindle microtubules. We demonstrate that the NE protein phosphatase, CNEP-1/CTDNEP1, controls de novo glycerolipid synthesis through lipin to prevent invasion of excess ER membranes into NE holes and a defective NE permeability barrier. Loss of NE adaptors for ESCRT-III exacerbates ER invasion and nuclear permeability defects in cnep-1 mutants, suggesting that ESCRTs restrict excess ER membranes during NE closure. Restoring glycerolipid synthesis in embryos deleted for CNEP-1 and ESCRT components rescued NE permeability defects. Thus, regulating the production and feeding of ER membranes into NE holes together with ESCRT-mediated remodeling is required for nuclear closure.

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