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 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 Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

2015 ◽  
Vol 112 (25) ◽  
pp. 7707-7712 ◽  
Author(s):  
Yusuke Ohno ◽  
Shota Nakamichi ◽  
Aya Ohkuni ◽  
Nozomi Kamiyama ◽  
Ayano Naoe ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Lipid Analysis ◽  
Skin Permeability ◽  
Carbon Chain Length ◽  
Permeability Barrier ◽  
Type I ◽  
P450 Gene ◽  
Barrier Formation

A skin permeability barrier is essential for terrestrial animals, and its impairment causes several cutaneous disorders such as ichthyosis and atopic dermatitis. Although acylceramide is an important lipid for the skin permeability barrier, details of its production have yet to be determined, leaving the molecular mechanism of skin permeability barrier formation unclear. Here we identified the cytochrome P450 gene CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22) as the long-sought fatty acid ω-hydroxylase gene required for acylceramide production. CYP4F22 has been identified as one of the autosomal recessive congenital ichthyosis-causative genes. Ichthyosis-mutant proteins exhibited reduced enzyme activity, indicating correlation between activity and pathology. Furthermore, lipid analysis of a patient with ichthyosis showed a drastic decrease in acylceramide production. We determined that CYP4F22 was a type I membrane protein that locates in the endoplasmic reticulum (ER), suggesting that the ω-hydroxylation occurs on the cytoplasmic side of the ER. The preferred substrate of the CYP4F22 was fatty acids with a carbon chain length of 28 or more (≥C28). In conclusion, our findings demonstrate that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase responsible for acylceramide production and provide important insights into the molecular mechanisms of skin permeability barrier formation. Furthermore, based on the results obtained here, we proposed a detailed reaction series for acylceramide production.

scholarly journals Hierarchical assembly of the eggshell and permeability barrier in C. elegans

2012 ◽  
Vol 198 (4) ◽  
pp. 731-748 ◽  
Author(s):  
Sara K. Olson ◽  
Garrett Greenan ◽  
Arshad Desai ◽  
Thomas Müller-Reichert ◽  
Karen Oegema
Keyword(s):  
Small Molecules ◽  
Molecular Mechanisms ◽  
Acyl Chain ◽  
Light And Electron Microscopy ◽  
Acid Synthesis ◽  
Permeability Barrier ◽  
Cortical Granules ◽  
Hierarchical Assembly ◽  
C Elegans ◽  
Separate Step

In metazoans, fertilization triggers the assembly of an extracellular coat that constitutes the interface between the embryo and its environment. In nematodes, this coat is the eggshell, which provides mechanical rigidity, prevents polyspermy, and is impermeable to small molecules. Using immunoelectron microscopy, we found that the Caenorhabditis elegans eggshell was composed of an outer vitelline layer, a middle chitin layer, and an inner layer containing chondroitin proteoglycans. The switch between the chitin and proteoglycan layers was achieved by internalization of chitin synthase coincident with exocytosis of proteoglycan-containing cortical granules. Inner layer assembly did not make the zygote impermeable as previously proposed. Instead, correlative light and electron microscopy demonstrated that the permeability barrier was a distinct envelope that formed in a separate step that required fatty acid synthesis, the sugar-modifying enzyme PERM-1, and the acyl chain transfer enzyme DGTR-1. These findings delineate the hierarchy of eggshell assembly and define key molecular mechanisms at each step.

scholarly journals Neuronally Produced Betaine Acts via a Novel Ligand Gated Ion Channel to Control Behavioural States

2021 ◽  
Author(s):  
Iris Hardege ◽  
Julia Morud ◽  
Jingfang Yu ◽  
Tatiana S Wilson ◽  
Frank Schroeder ◽  
...  
Keyword(s):  
Nervous System ◽  
Ion Channel ◽  
Molecular Mechanisms ◽  
Amino Acid Derivative ◽  
Single Pair ◽  
Complex Behaviour ◽  
Functional Roles ◽  
C Elegans ◽  
Nematode Worm ◽  
Control Complex

Trimethyl glycine, or betaine, is an amino acid derivative found in diverse organisms, from bacteria to plants and animals. It can function as an osmolyte to protect cells against osmotic stress, and building evidence suggests betaine may also play important functional roles in the nervous system. However, despite growing interest in betaine's roles in the nervous system, few molecular mechanisms have been elucidated. Here we identify the expression of betaine synthesis pathway genes in the nervous system of the nematode worm, C. elegans. We show that betaine, produced in a single pair of interneurons, the RIMs, can control complex behavioural states. Moreover, we also identify and characterise a new betaine-gated inhibitory ligand gated ion channel, LGC-41, which is required for betaine related behavioural changes. Intriguingly we observed expression of LGC-41 in punctate structures across several sensory and interneurons, including those synaptically connected to the RIMs. Our data presents a neuronal molecular mechanism for the action of betaine, via a specific receptor, in the control of complex behaviour within the nervous system of C. elegans. This may suggest a much broader role for betaine in the regulation of animal nervous systems than previously recognised.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells

2019 ◽  
Vol 14 (5) ◽  
pp. 405-420 ◽  
Author(s):  
Eduardo Alvarado-Ortiz ◽  
Miguel Á. Sarabia-Sánchez ◽  
Alejandro García-Carrancá
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Tumor Biology ◽  
Molecular Tools ◽  
Recent Past ◽  
Functional Roles ◽  
Cellular Population ◽  
Cellular Markers ◽  
A Minor

Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.

scholarly journals Genome-Wide Mapping of Histone H3 Lysine 4 Trimethylation (H3K4me3) and Its Involvement in Fatty Acid Biosynthesis in Sunflower Developing Seeds

Plants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 706
Author(s):  
Antonio J. Moreno-Pérez ◽  
Raquel Martins-Noguerol ◽  
Cristina DeAndrés-Gil ◽  
Mónica Venegas-Calerón ◽  
Rosario Sánchez ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Chromatin Remodeling ◽  
Molecular Mechanisms ◽  
Acid Metabolism ◽  
Fatty Acid Biosynthesis ◽  
Acid Synthesis ◽  
Sunflower Seeds ◽  
Acid Biosynthesis ◽  
Functional Regions ◽  
Genome Wide

Histone modifications are of paramount importance during plant development. Investigating chromatin remodeling in developing oilseeds sheds light on the molecular mechanisms controlling fatty acid metabolism and facilitates the identification of new functional regions in oil crop genomes. The present study characterizes the epigenetic modifications H3K4me3 in relationship with the expression of fatty acid-related genes and transcription factors in developing sunflower seeds. Two master transcriptional regulators identified in this analysis, VIV1 (homologous to Arabidopsis ABI3) and FUS3, cooperate in the regulation of WRINKLED 1, a transcriptional factor regulating glycolysis, and fatty acid synthesis in developing oilseeds.

scholarly journals Changes on proteomic and metabolomic profile in serum of mice induced by chronic exposure to tramadol

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shukun Jiang ◽  
Guojie Liu ◽  
Huiya Yuan ◽  
Enyu Xu ◽  
Wei Xia ◽  
...  
Keyword(s):  
Chronic Exposure ◽  
Molecular Mechanisms ◽  
Fatty Acid Biosynthesis ◽  
Serum Proteins ◽  
Enzyme Inhibitor ◽  
Bile Secretion ◽  
Control Group ◽  
Protein Digestion ◽  
Metabolomic Profile ◽  
Apolipoprotein C

AbstractTramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Limited literature available indicates the change of proteomic profile after chronic exposure to tramadol. In this study, we analyzed the proteomic and metabolomic profile by TMT-labeled quantitative proteomics and untargeted metabolomics between the tramadol and the control group. Proteomic analysis revealed 31 differential expressed serum proteins (9 increased and 22 decreased) in tramadol-treated mice (oral, 50 mg/kg, 5 weeks) as compared with the control ones. Bioinformatics analysis showed that the dysregulated proteins mainly included: enzyme inhibitor-associated proteins (i.e. apolipoprotein C-III (Apoc-III), alpha-1-antitrypsin 1–2 (Serpina 1b), apolipoprotein C-II (Apoc-II), plasma protease C1 inhibitor, inter-alpha-trypsin inhibitor heavy chain H3 (itih3)); mitochondria-related proteins (i.e. 14-3-3 protein zeta/delta (YWHAZ)); cytoskeleton proteins (i.e. tubulin alpha-4A chain (TUBA4A), vinculin (Vcl)). And we found that the differential expressed proteins mainly involved in the pathway of the protein digestion and absorption. Metabolomics analysis revealed that differential expressed metabolites mainly involved in protein ingestion and absorption, fatty acid biosynthesis, steroid hormone biosynthesis and bile secretion. Our overall findings revealed that chronic exposure to tramadol changed the proteomic and metabolomic profile of mice. Moreover, integrated proteomic and metabolomic revealed that the protein digestion and absorption is the common enrichment KEGG pathway. Thus, the combination of proteomics and metabolomics opens new avenues for the research of the molecular mechanisms of tramadol toxicity.

scholarly journals Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

2021 ◽  
pp. 1-9
Author(s):  
Dayana Torres Valladares ◽  
Sirisha Kudumala ◽  
Murad Hossain ◽  
Lucia Carvelli
Keyword(s):  
Caenorhabditis Elegans ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Genetic Model ◽  
In Vivo Model ◽  
C Elegans ◽  
Hyperactivity Disorder ◽  
In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

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