| 1. |
- Herdenberg, Carl, et al.
(författare)
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LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes
- 2021
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-β) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease.
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| 2. |
- Nilsson, Lars, et al.
(författare)
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C. elegans TAT-6, a putative aminophospholipid translocase, is expressed in sujc cells in the hermaphrodite gonad
- 2021
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Ingår i: microPublication biology. - : Caltech Library. - 2578-9430.
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Tidskriftsartikel (refereegranskat)abstract
- In healthy eukaryotic cells, the two leaflets that make up plasma membranes are highly asymmetric with respect to the lipids they contain. In both unicellular eukaryotes and metazoans, the asymmetry in the distribution of aminophospholipids is maintained by P4-family transmembrane ATPases, which catalyze the movement of selected phospholipids from the outer leaflet to the inner. C. elegans has six P4-family ATPases, TAT-1 - TAT-6. TAT-1 - TAT-5 are expressed in many tissues and cells. Here we report that, in contrast, TAT-6 is much less broadly expressed and that, within the somatic gonad, expression of TAT-6 reporters is restricted to the spermathecal-uterine core cell (sujc) cells.
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| 3. |
- Pu, Longjun, 1990-
(författare)
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A molecular exploration of sensory responses in c. elegans
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sensation provides a pivotal ability, allowing animals to survive in complex environments. The cues sensed by animals are represented by external stimuli and internal signals. However, the mechanisms mediating sensations in molecular and cellular level are still not well-studied. In this thesis, by using free-living nematodes C. elegans with relatively simple nerve system, we are trying to get better understandings of molecular mechanisms by which animals sense and interpret external cues and internal signals.G protein-coupled receptors (GPCRs), as one of the major families of transmembrane proteins, participate in a variety of physiological responses to both external stimuli and internal cues. Previous studies have shown that GPCR signals are broadly involved in many processes in C. elegans, such as olfactory sensing, nociceptive responses, social behavior, pathogen responses, and mating. However, the complexity and diversity of GPCRs pose significant challenges to systematic dissection of their function as well as identification of receptor-ligand pairs which play crucial roles for animals´ sensory behaviors. Interestingly, the genome of C. elegans encodes one of the largest GPCR repertoires among any sequenced organisms, indicating a dramatical expansion and high degree of gene redundancy. To comprehensively dissect GPCR signaling in C. elegans and gain more insights into their roles in sensations, we developed an approach by employing CRISPR/Cas9-based gene editing to mutate closely related GPCRs and neuropeptide genes (internal signals) in a single strain on a genome-wide scale, resulting in disrupting nearly all the GPCR and neuropeptide genes (more than 1800 genes in total) and eliminating high degree of gene redundancy as well. Then using these two genetic libraries, we successfully identified neuropeptide (FLP -1) and cognate receptors (DMSR-4, DMSR-7 and DMSR-8) required for hypoxia-evoked locomotory responses, obtained a set of novel regulators of the pathogen-induced immune response including FMI-1 and DOP-6, and especially identified receptors (SRX-64) in AWA neurons for the volatile odorant pyrazine and redundant receptors (SRX-1, SRX-2 and SRX-3) in AWCOFF neuron for 2,3-pentanedione.In nature, animals often experience and sense constantly changing gas environments. And human bodies also generate internal gas as gasotransmitters for signal transduction, such as CO, NO and H2S. For the mechanism governing sensory and adaptive responses to different gaseous cues, extensive studies are still needed. Here, taking advantage of the robust locomotory responses to H2S in C. elegans, we delineated the molecular mechanisms of H2S sensation and adaptation. We found that C. elegans exhibited transiently increased locomotory and turning activity as a strategy to escape the noxious H2S. The behavioral responses to H2S were modulated by a complex network of signaling pathways, ranging from cyclic GMP signaling in ciliated sensory neurons, calcineurin, nuclear hormone receptors, to the major starvation regulators such as insulin and TGF-β signaling. Prolonged exposure to H2S robustly evoked H2S detoxification and reprogrammed gene expression, where genes involved in iron homeostasis, including ftn-1 and smf-3, were robustly modified, implying that labile iron levels are affected by H2S. In addition, the roles of labile iron for modulating H2S response were further investigated by using genetic studies and chemical applications. Interestingly, the response to H2S was substantially affected by the ambient O2 levels and their prior experience in low O2 environments, suggesting an intricate interplay between O2 and H2S sensing. The crosstalk is often seen between different experiences and sensations. In addition to the interplay between O2 and H2S sensing, we found hypoxia challenge could induce food leaving behavior in C. elegans. The alteration of food behavior by hypoxia experience was independent of the known mechanisms involved in O2 response, including pathways in acute hypoxia and HIF-1 signaling for chronic hypoxia response. The robust failure of induced food avoidance in egl-3 and egl-21 mutants suggested that neuropeptidergic signaling was required for this response. And future work is needed for comprehensively understanding the roles of neuropeptide signaling in the crosstalk between hypoxia experience and food leaving behavior.In summary, our studies shed light on the molecular and cellular mechanisms of how animals sense and interpret the signals, allowing them to survive in a complex environment niche. More specifically, 1) we demonstrated the dissection of genetic landscape of GPCR signaling through phenotypic profiling in C. elegans. And as a powerful genetic resource, our libraries can greatly expedite the analyses of GPCR signaling in multiple additional contexts. 2) we provided molecular insights into how C. elegans detects and adapts its response to H2S and modulates behaviors through ambient environment and experience.
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| 4. |
- Rahmani, Shapour, et al.
(författare)
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EGL-4 promotes turning behavior of C. elegans males during mating
- 2021
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Ingår i: microPublication biology. - : Caltech Library. - 2578-9430.
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Tidskriftsartikel (refereegranskat)abstract
- During mating, C. elegans males whose tails have reached the head or tail of their intended mates are able to switch to scanning the other side by performing a turn during which the male's tail curls ventrally all the while keeping in contact with the hermaphrodite. The ability to execute turns efficiently is dependent upon serotonergic neurons in the posterior ventral nerve cord that stimulate diagonal muscles by activating a serotonin receptor, SER-1. Here we show that turning behavior is abnormal in males lacking a cGMP-dependent protein kinase, EGL-4. egl-4 mutant males are also resistant to ventral tail curling induced by exogenous serotonin.
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| 5. |
- Rahmani, Shapour, 1975-
(författare)
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Studies on lipid transport and extracellular vesicle production in Caenorhabditis elegans ciliated neurons
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The cilium is a protrusion of cell membrane. Both the protein and lipid contents of cilia are different from those of other parts of the cell membrane. While the transport of proteins into and out of cilia has been intensively studied, much less is known about how the lipid content of ciliary membranes is regulated. TAT-6 is a P4-family ATPase that is expressed in C. elegans ciliated neurons whose endings are exposed to the environment. To study the function of TAT-6 and that other translocases in lipid transport in C. elegans ciliated neurons, I developed a technique to allow labelling of cilia with lipids. For the first time I used fusogenic liposomes to study the roles of all the TAT proteins in this organism in maintaining the lipid asymmetry in this organelle. Assessment the cilia with these liposomes showed that TAT-5 and TAT-1 translocase activities promote the transport of phosphatidylethanolamine (PE) and phosphatidylserine (PS) respectively and TAT-6 has an overlapping function in transporting both phospholipds. In C. elegans males, certain ciliated neurons release extracellular vesicles (EVs). The cilium is a site of EV biogenesis and shedding. I found that ciliated neurons in tat-6 mutant males produced significantly fewer EVs than those in wild type. tat-1, tat-5 and pad-1 mutants, however, produced far more EVs than those in wild type. PPK-3, CUP-5 and LMP-1 are proteins necessary for endolysosomal trafficking and lysosomes biogenesis, a process in which TAT-1 has previously been shown to function in C. elegans intestinal cells. I found that, like tat-1 mutants, ppk-3, lmp-1 and cup-5 mutant males release significantly greater numbers of EVs from cilia compared with wild-type. I found that increasing and decreasing the cGMP signaling cause defects in the response and turning behavior in male C. elegans respectively. Exposing wild-type males to high levels of 8-Bromoguanosine 3′,5′-cyclic monophosphate strongly reduced response behavior. Males mutant for odr-3, which encodes a G protein were defective in response. Overall my investigations indicate that the regulation of lipid asymmetry and phospholipid transport is required for proper cilia function in C. elegans, that intercellular trafficking and lipid composition have important roles in EVs biogenesis, and that different TAT proteins can affect the size and number of EVs produced. I also showed that in male animals, cGMP is one of the mediators in mating transduction signal and that a high level of cGMP inhibits mating response behavior in male C. elegans.
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| 6. |
- Zhao, Lina, 1990-
(författare)
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Oxygen sensing in Caenorhabditis elegans
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sufficient supply of oxygen (O2) to tissue is essential for survival of aerobicanimals. In mammals, there are constant homeostatic regulation mechanisms that act on different time scales to maintain optimal O2 delivery to tissues. The ability to detect and respond to acute oxygen shortages is indispensable to aerobic life. However, the molecular mechanisms and circuits underlying this capacity are poorly understood.We characterize the locomotory response of feeding Caenorhabditis elegans (C. elegans) to 1% O2. Acute hypoxia triggers a bout of turning maneuvers followed by a persistent switch to rapid forward movement as animals seek to avoid and escape hypoxia. Increasing cGMP signaling inhibits escape from 1% O2, and that cGMP activates the protein kinase G, EGL-4, which in turn enhances neuroendocrine secretion to inhibit acute response to 1% O2. A primary source of cGMP is the guanylyl cyclase, GCY-28. In addition, increasing mitochondrial reactive oxygen species (ROS), abrogate acute hypoxia response. Up-regulation of mitochondrial ROS increases cGMP levels, which contribute to the reduced hypoxia response. Our results implicate ROS and precise regulation of intracellular cGMP in the modulation of acute response to hypoxia by C. elegans.In addition, we found that FMRFamide-related peptides FLP-1 plays a role in hypoxia evoked locomotory response. Our data showed that FLP-1 secretion from AVK interneurons acts on AVA and other neurons through DMSR-4, DMSR7, and DMSR-8 GPCR receptors to maintain baseline speed and to promote locomotory response to hypoxia.We also found that hypoxia could induce food leaving behavior in C. elegans. Animals quickly escaped from the bacterial lawn when exposed to 1% O2. The known O2 response mechanisms cannot explain this phenotype, instead, neuropeptidergic signalling seems to be required for this behaviour.It's known that pro-inflammatory cytokine ILC-17.1, the homologue of mammalian IL-17s, act as a neuromodulator involved in hyperoxia sensing in C. elegans. We found that it was not involved in acute hypoxia response. Instead, ILC-17.1 could modulate lifespan and damage defense mechanisms against stress in C. elegans by triggering an inhibitory network to constrain the activity of the nuclear hormone receptor, NHR-49.In summary, our research can provide molecular and neurological understanding of how O2 is sensed by animals. Additionally, it further emphasis C. elegans as a good model to understand oxygen sensing
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