2K Papers found (0.016 seconds)

Ma L et al. (2020) J Cell Biol "Membrane fusion drives pronuclear meeting in the one-cell embryo."

[

J Cell Biol,

2020]

The mechanisms that control how the two parental pronuclei fuse in the first mitosis of the embryo are poorly understood. In this issue, Rahman et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.201909137) found that membrane fusion between pronuclear envelopes, followed by fenestration, promotes pronuclear fusion.

Ma L et al. (2012) PLoS Genet "The Caenorhabditis elegans gene mfap-1 encodes a nuclear protein that affects alternative splicing."

Horvitz HR, Luo J, Teng Y, Ma L, Huang L, Gao X

[

PLoS Genet,

2012]

RNA splicing is a major regulatory mechanism for controlling eukaryotic gene expression. By generating various splice isoforms from a single pre-mRNA, alternative splicing plays a key role in promoting the evolving complexity of metazoans. Numerous splicing factors have been identified. However, the in vivo functions of many splicing factors remain to be understood. In vivo studies are essential for understanding the molecular mechanisms of RNA splicing and the biology of numerous RNA splicing-related diseases. We previously isolated a Caenorhabditis elegans mutant defective in an essential gene from a genetic screen for suppressors of the rubberband Unc phenotype of unc-93(e1500) animals. This mutant contains missense mutations in two adjacent codons of the C. elegans microfibrillar-associated protein 1 gene mfap-1. mfap-1(n4564 n5214) suppresses the Unc phenotypes of different rubberband Unc mutants in a pattern similar to that of mutations in the splicing factor genes uaf-1 (the C. elegans U2AF large subunit gene) and sfa-1 (the C. elegans SF1/BBP gene). We used the endogenous gene tos-1 as a reporter for splicing and detected increased intron 1 retention and exon 3 skipping of tos-1 transcripts in mfap-1(n4564 n5214) animals. Using a yeast two-hybrid screen, we isolated splicing factors as potential MFAP-1 interactors. Our studies indicate that C. elegans mfap-1 encodes a splicing factor that can affect alternative splicing.

Ma L et al. (2011) RNA "In vivo effects on intron retention and exon skipping by the U2AF large subunit and SF1/BBP in the nematode Caenorhabditis elegans."

Horvitz HR, Tan Z, Hoersch S, Ma L, Teng Y

[

RNA,

2011]

The in vivo analysis of the roles of splicing factors in regulating alternative splicing in animals remains a challenge. Using a microarray-based screen, we identified a Caenorhabditis elegans gene, tos-1, that exhibited three of the four major types of alternative splicing: intron retention, exon skipping, and, in the presence of U2AF large subunit mutations, the use of alternative 3' splice sites. Mutations in the splicing factors U2AF large subunit and SF1/BBP altered the splicing of tos-1. 3' splice sites of the retained intron or before the skipped exon regulate the splicing pattern of tos-1. Our study provides in vivo evidence that intron retention and exon skipping can be regulated largely by the identities of 3' splice sites.

Ma L et al. (2009) PLoS Genet "Mutations in the Caenorhabditis elegans U2AF large subunit UAF-1 alter the choice of a 3' splice site in vivo."

Ma L, Horvitz HR

[

PLoS Genet,

2009]

The removal of introns from eukaryotic RNA transcripts requires the activities of five multi-component ribonucleoprotein complexes and numerous associated proteins. The lack of mutations affecting splicing factors essential for animal survival has limited the study of the in vivo regulation of splicing. From a screen for suppressors of the Caenorhabditis elegans unc-93(e1500) rubberband Unc phenotype, we identified mutations in genes that encode the C. elegans orthologs of two splicing factors, the U2AF large subunit (UAF-1) and SF1/BBP (SFA-1). The uaf-1(n4588) mutation resulted in temperature-sensitive lethality and caused the unc-93 RNA transcript to be spliced using a cryptic 3' splice site generated by the unc-93(e1500) missense mutation. The sfa-1(n4562) mutation did not cause the utilization of this cryptic 3' splice site. We isolated four uaf-1(n4588) intragenic suppressors that restored the viability of uaf-1 mutants at 25 degrees C. These suppressors differentially affected the recognition of the cryptic 3' splice site and implicated a small region of UAF-1 between the U2AF small subunit-interaction domain and the first RNA recognition motif in affecting the choice of 3' splice site. We constructed a reporter for unc-93 splicing and using site-directed mutagenesis found that the position of the cryptic splice site affects its recognition. We also identified nucleotides of the endogenous 3' splice site important for recognition by wild-type UAF-1. Our genetic and molecular analyses suggested that the phenotypic suppression of the unc-93(e1500) Unc phenotype by uaf-1(n4588) and sfa-1(n4562) was likely caused by altered splicing of an unknown gene. Our observations provide in vivo evidence that UAF-1 can act in regulating 3' splice-site choice and establish a system that can be used to investigate the in vivo regulation of RNA splicing in C. elegans.

Ma L et al. (2017) Eur J Pharmacol "Caenorhabditis elegans as a model system for target identification and drug screening against neurodegenerative diseases."

Huang K, Zhao Y, Chen Y, Ma L, Cheng B, Peng A

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Eur J Pharmacol,

2017]

Over the past decades, C. elegans has been widely used as a model system because of its small size, transparent body, short generation time and lifespan (~3 days and 3 weeks, respectively), completely sequenced genome and tractability to genetic manipulation. Protein misfolding and aggregation are key pathological features in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Animal models, including Caenorhabditis elegans (C. elegans), have been extensively used to discover and validate new drugs against neurodegenerative diseases. The well-defined and genetically tractable nervous system of C. elegans offers an effective model to explore basic mechanistic pathways of neurodegenerative diseases. Recent progress in high-throughput drug screening also provides a powerful approach for identifying chemical modulators of biological processes. Here, we summarize the latest progress of using C. elegans as a model system for target identification and drug screening in neurodegenerative diseases.

Ma L et al. (2025) Anal Chem "Unraveling the Synergistic Neuroprotective Mechanism of Natural Drug Candidates Targeting TRPV1 and TRPM8 on an Ischemic Stroke."

Ma C, Li N, Wang J, Wang Z, Ma L, Li M, Du Y, Wei Y, Wu Z

[

Anal Chem,

2025]

The development of multitargeted drugs is urgent for ischemic stroke. TRPV1 and TRPM8 are important targets of ischemic stroke. Previous drug candidate screening has identified that muscone, l-borneol, and ferulic acid may target TRPV1 and TRPM8 for ischemic stroke. However, the mechanisms of these drug candidates on targets were ill-informed. Therefore, firstly, a tongue-tissue biosensor was constructed. It explored the activation or inhibition mechanisms of drug candidates targeting TRPV1 and TRPM8 in a near-physiological environment. It was found that muscone could specifically inhibit TRPM8 and selectively activate TRPV1, while l-borneol exhibited the opposite effect. It suggested a synergistic network between these two drug candidates. Furthermore, more selective protein biosensors were developed to delve deeper into the synergistic mechanisms. A strong synergistic effect of muscone and l-borneol was proved. Molecular docking revealed that the synergistic effect was caused by different action sites, respectively. Subsequently, the synergistic effect of muscone and l-borneol was further confirmed by hypoxic nerve injury models of Caenorhabditis elegans (C. elegans) and antithrombus and anti-ischemic models of zebrafish. Ultimately, through nontargeted metabolomics, it was found that muscone and l-borneol mainly regulated Ca2+ concentration and energy metabolism by pathways such as purine and amino acid metabolisms. In conclusion, this research identified critical targets and synergistic drug candidates for multitarget neuroprotection of ischemic stroke. In addition, it has systemically demonstrated the feasibility of the integration of tissue/protein biosensors and metabolomics for the research and development of multitarget drugs. Compared to other screening and validation methods for drugs and targets, the biosensors we developed not only achieved higher sensitivity and specificity in complex physiological environments, ensuring a wider detection range, but also greatly saved biological samples. Simultaneously, they could be extended to other complex systems, such as biomarker screening in clinical samples and exosomes isolated from stem cells.

Ma L et al. (2023) Toxicol Res (Camb) "High-throughput transcriptome sequencing reveals the protective role of adenosine receptor-related genes in paraquat-exposed Caenorhabditis elegans."

Ling C, Hu S, Chen C, Ye S, Ma L

[

Toxicol Res (Camb),

2023]

This study sought to identify the genes associated with adenosine's protective action against paraquat (PQ)-induced oxidative stress via the adenosine receptor (ADOR-1) in Caenorhabditis elegans (C. elegans). The C. elegans was divided into 3 groups-2 groups exposed to PQ, one in presence, and one in absence of adenosine-and a control group that was not treated. Each group's total RNA was extracted and sequenced. When the transcriptomes of these groups were analyzed, several genes were found to be differently expressed. These differentially expressed genes were significantly enriched in adenosine-response biological processes and pathways, including gene ontology terms related to neuropeptide and kyoto encyclopedia of genes and genomes pathways associated to cAMP pathway regulator activity. Quantitative reverse-transcription PCR confirmed that G-protein-coupled receptors signaling pathway involving dop-1, egl-30, unc-13, kin-1, and goa-1 genes may play crucial roles in modulating adenosine's protective action. Interestingly, there are no significant variations in the expression of the ador-1 gene across the 3 treatments, thereby indicating that adenosine receptor exerts a consistent and stable influence on its related pathways irrespective of the presence or absence of PQ. Furthermore, the wild-type group with ador-1 gene has higher survival rate than that of the ador-1-/RNA interference group while treated with PQ in the presence of adenosine. Conclusively, our study uncovered a number of novel PQ-response genes and adenosine receptor-related genes in C. elegans, which may function as major regulators of PQ-induced oxidative stress and indicate the possible protective effects of adenosine.

Ma L et al. (2024) Genetics "FLN-2 functions in parallel to linker of nucleoskeleton and cytoskeleton complexes and CDC-42/actin pathways during P-cell nuclear migration through constricted spaces in Caenorhabditis elegans."

Starr DA, Chang YT, Kuhn J, Elnatan D, Luxton GWG, Ma L

[

Genetics,

2024]

Nuclear migration through narrow constrictions is important for development, metastasis, and proinflammatory responses. Studies performed in tissue culture cells have implicated linker of nucleoskeleton and cytoskeleton (LINC) complexes, microtubule motors, the actin cytoskeleton, and nuclear envelope repair machinery as important mediators of nuclear movements through constricted spaces. However, little is understood about how these mechanisms operate to move nuclei in vivo. In Caenorhabditis elegans larvae, six pairs of hypodermal P cells migrate from lateral to ventral positions through a constricted space between the body wall muscles and the cuticle. P-cell nuclear migration is mediated in part by LINC complexes using a microtubule-based pathway and by an independent CDC-42/actin-based pathway. However, when both LINC complex and actin-based pathways are knocked out, many nuclei still migrate, suggesting the existence of additional pathways. Here, we show that FLN-2 functions in a third pathway to mediate P-cell nuclear migration. The predicted N-terminal actin-binding domain in FLN-2 that is found in canonical filamins is dispensable for FLN-2 function; this and structural predictions suggest that FLN-2 does not function as a filamin. The immunoglobulin-like repeats 4-8 of FLN-2 were necessary for P-cell nuclear migration. Furthermore, in the absence of the LINC complex component unc-84, fln-2 mutants had an increase in P-cell nuclear rupture. We conclude that FLN-2 functions to maintain the integrity of the nuclear envelope in parallel with the LINC complex and CDC-42/actin-based pathways to move P-cell nuclei through constricted spaces.

Eric Miska et al. (2002) European Worm Meeting "Functional analysis of the micro RNA genes of C. elegans"

Allison Abbott, Bob Horvitz, Nelson C Lau, Victor Ambros, Eric Miska, David P Bartel, Ezequiel Alvarez-Saavedra

[

European Worm Meeting,

2002]

* HHMI and Dept. Biology, MIT, Cambridge, MA 02139, USA Dept. Genetics, Dartmouth Medical School, Hanover, NH, 03755, USA # Whitehead Institute for Biomedical Research and Dept. Biology, MIT, Cambridge, MA 02142, USA

Thosapornvichai T et al. (2022) Environ Toxicol Pharmacol "Mitochondrial daysfunction from malathion and chlorpyrifos exposure is associated with degeneration of GABAergic neurons in Caenorhabditis elegans."

Jensen LT, Thosapornvichai T, Huangteerakul C, Jensen AN

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Environ Toxicol Pharmacol,

2022]

Toxicity resulting from off-target effects, beyond acetylcholine esterase inhibition, for the commonly used organophosphate (OP) insecticides chlorpyrifos (CPS) and malathion (MA) was investigated using Saccharomyces cerevisiae and Caenorhabditis elegans model systems. Mitochondrial damage and dysfunction were observed in yeast following exposure to CPS and MA, suggesting this organelle is a major target. In the C. elegans model, the mitochondrial unfolded protein response pathway showed the most robust induction from CPS and MA treatment among stress responses examined. GABAergic neurodegeneration was observed with CPS and MA exposure. Impaired movement observed in C. elegans exposed to CPS and MA may be the result of motor neuron damage. Our analysis suggests that stress from CPS and MA results in mitochondrial dysfunction, with GABAergic neurons sensitized to these effects. These findings may aid in the understanding of toxicity from CPS and MA from high concentration exposure leading to insecticide poisoning.

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