Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

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A role for Rab5 in structuring the endoplasmic reticulum

The Journal of Cell Biology ◽

10.1083/jcb.200701139 ◽

2007 ◽

Vol 178 (1) ◽

pp. 43-56 ◽

Cited By ~ 128

Author(s):

Anjon Audhya ◽

Arshad Desai ◽

Karen Oegema

Keyword(s):

Endoplasmic Reticulum ◽

Caenorhabditis Elegans ◽

Nuclear Envelope ◽

Rab Gtpases ◽

C Elegans ◽

Rab Family ◽

Kinetics Of

The endoplasmic reticulum (ER) is a contiguous network of interconnected membrane sheets and tubules. The ER is differentiated into distinct domains, including the peripheral ER and nuclear envelope. Inhibition of two ER proteins, Rtn4a and DP1/NogoA, was previously shown to inhibit the formation of ER tubules in vitro. We show that the formation of ER tubules in vitro also requires a Rab family GTPase. Characterization of the 29 Caenorhabditis elegans Rab GTPases reveals that depletion of RAB-5 phenocopies the defects in peripheral ER structure that result from depletion of RET-1 and YOP-1, the C. elegans homologues of Rtn4a and DP1/NogoA. Perturbation of endocytosis by other means did not affect ER structure; the role of RAB-5 in ER morphology is thus independent of its well-studied requirement for endocytosis. RAB-5 and YOP-1/RET-1 also control the kinetics of nuclear envelope disassembly, which suggests an important role for the morphology of the peripheral ER in this process.

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The glycomes of Caenorhabditis elegans and other model organisms

Biochemical Society Symposium ◽

10.1042/bss0690117 ◽

2002 ◽

Vol 69 ◽

pp. 117-134 ◽

Cited By ~ 47

Author(s):

Stuart M. Haslam ◽

David Gems ◽

Howard R. Morris ◽

Anne Dell

Keyword(s):

Caenorhabditis Elegans ◽

Current Knowledge ◽

Structural Data ◽

Model Organisms ◽

Entire Genome ◽

C Elegans ◽

The Face ◽

Area Of Concern ◽

Nematode Worm

There is no doubt that the immense amount of information that is being generated by the initial sequencing and secondary interrogation of various genomes will change the face of glycobiological research. However, a major area of concern is that detailed structural knowledge of the ultimate products of genes that are identified as being involved in glycoconjugate biosynthesis is still limited. This is illustrated clearly by the nematode worm Caenorhabditis elegans, which was the first multicellular organism to have its entire genome sequenced. To date, only limited structural data on the glycosylated molecules of this organism have been reported. Our laboratory is addressing this problem by performing detailed MS structural characterization of the N-linked glycans of C. elegans; high-mannose structures dominate, with only minor amounts of complex-type structures. Novel, highly fucosylated truncated structures are also present which are difucosylated on the proximal N-acetylglucosamine of the chitobiose core as well as containing unusual Fucα1–2Gal1–2Man as peripheral structures. The implications of these results in terms of the identification of ligands for genomically predicted lectins and potential glycosyltransferases are discussed in this chapter. Current knowledge on the glycomes of other model organisms such as Dictyostelium discoideum, Saccharomyces cerevisiae and Drosophila melanogaster is also discussed briefly.

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Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽

10.1039/c5ra13546j ◽

2015 ◽

Vol 5 (95) ◽

pp. 77706-77715 ◽

Cited By ~ 4

Author(s):

Supinder Kaur ◽

Aamir Nazir

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Caenorhabditis Elegans ◽

Potential Role ◽

Alpha Synuclein ◽

C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

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Autophagosomes fuse to phagosomes and play important roles in the degradation of apoptotic cells in Caenorhabditis elegans

10.1101/2021.07.16.452694 ◽

2021 ◽

Author(s):

Omar Pena-Ramos ◽

Lucia Chiao ◽

Xianghua Liu ◽

Tianyou Yao ◽

Henry He ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Small Gtpase ◽

Apoptotic Cells ◽

Phagosome Maturation ◽

Double Membrane ◽

C Elegans ◽

Intracellular Organelles ◽

Intracellular Vesicles ◽

Cellular Components

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. In the nematode Caenorhabditis elegans, 113 somatic cells undergo apoptosis during embryogenesis and are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells in C. elegans embryos using a real-time imaging technique. Specifically, double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner membrane to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant delays in the degradation of apoptotic cells, demonstrating the important contribution of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, CED-1s adaptor CED-6, and the large GTPase dynamin (DYN-1) promote the recruitment of autophagosomes to phagosomes. Moreover, the subsequent fusion of autophagosomes with phagosomes requires the functions of the small GTPase RAB-7 and the HOPS complex. Our findings reveal that, unlike the single-membrane, LC3- associated phagocytosis (LAP) vesicles reported for mammalian phagocytes, canonical autophagosomes function in the clearance of C. elegans apoptotic cells. These findings add autophagosomes to the collection of intracellular organelles that contribute to phagosome maturation, identify novel crosstalk between the autophagy and phagosome maturation pathways, and discover the upstream factors that initiate this crosstalk.

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The genetic and RFLP characterization of the left end of linkage group III in Caenorhabditis elegans

Genome ◽

10.1139/g93-096 ◽

1993 ◽

Vol 36 (4) ◽

pp. 712-724 ◽

Cited By ~ 2

Author(s):

Dave Pilgrim

Keyword(s):

Caenorhabditis Elegans ◽

Linkage Group ◽

Genetic Map ◽

Physical Map ◽

Group Iii ◽

C Elegans ◽

Genomic Regions ◽

Caenorhabditis Elegans Genome ◽

Selection Of

A genetic approach was taken to identify new transposable element Tc1 -dependent polymorphisms on the left end of linkage group III in the nematode Caenorhabditis elegans. The cloning of the genomic DNA surrounding the Tc1 allowed the selection of overlapping clones (from the collection being used to assemble the physical map of the C. elegans genome). A contig of approximately 600–800 kbp in the region has been identified, the genetic map of the region has been refined, and 10 new RFLPs as well as at least four previously characterized genetic loci have been positioned onto the physical map, to the resolution of a few cosmids. This analysis demonstrated the ability to combine physical and genetic mapping for the rapid analysis of large genomic regions (0.5–1 Mbp) in genetically amenable eukaryotes.Key words: Caenorhabditis elegans, genome analysis, RFLP, physical map, genetic map.

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Baculovirus expression of two protein disulphide isomerase isoforms from Caenorhabditis elegans and characterization of prolyl 4-hydroxylases containing one of these polypeptides as their β subunit

Biochemical Journal ◽

10.1042/bj3170721 ◽

1996 ◽

Vol 317 (3) ◽

pp. 721-729 ◽

Cited By ~ 26

Author(s):

Johanna VEIJOLA ◽

Pia ANNUNEN ◽

Peppi KOIVUNEN ◽

Antony P. PAGE ◽

Taina PIHLAJANIEMI ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Cloning And Expression ◽

Β Subunit ◽

Α Subunit ◽

Protein Disulphide Isomerase ◽

C Elegans ◽

Baculovirus Expression ◽

Expression Studies ◽

Α Subunits

Protein disulphide isomerase (PDI; EC 5.3.4.1) is a multifunctional polypeptide that is identical to the β subunit of prolyl 4-hydroxylases. We report here on the cloning and expression of the Caenorhabditis elegans PDI/β polypeptide and its isoform. The overall amino acid sequence identity and similarity between the processed human and C. elegans PDI/β polypeptides are 61% and 85% respectively, and those between the C. elegans PDI/β polypeptide and the PDI isoform 46% and 73%. The isoform differs from the PDI/β and ERp60 polypeptides in that its N-terminal thioredoxin-like domain has an unusual catalytic site sequence -CVHC-. Expression studies in insect cells demonstrated that the C. elegans PDI/β polypeptide forms an active prolyl 4-hydroxylase α2β2 tetramer with the human α subunit and an αβ dimer with the C. elegans α subunit, whereas the C. elegans PDI isoform formed no prolyl 4-hydroxylase with either α subunit. Removal of the 32-residue C-terminal extension from the C. elegans α subunit totally eliminated αβ dimer formation. The C. elegans PDI/β polypeptide formed less prolyl 4-hydroxylase with both the human and C. elegans α subunits than did the human PDI/β polypeptide, being particularly ineffective with the C. elegans α subunit. Experiments with hybrid polypeptides in which the C-terminal regions had been exchanged between the human and C. elegans PDI/β polypeptides indicated that differences in the C-terminal region are one reason, but not the only one, for the differences in prolyl 4-hydroxylase formation between the human and C. elegans PDI/β polypeptides. The catalytic properties of the C. elegans prolyl 4-hydroxylase αβ dimer were very similar to those of the vertebrate type II prolyl 4-hydroxylase tetramer, including the Km for the hydroxylation of long polypeptide substrates.

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Genes necessary for C. elegans cell and growth cone migrations

Development ◽

10.1242/dev.124.9.1831 ◽

1997 ◽

Vol 124 (9) ◽

pp. 1831-1843 ◽

Cited By ~ 20

Author(s):

W.C. Forrester ◽

G. Garriga

Keyword(s):

Cell Fate ◽

Single Gene ◽

Growth Cones ◽

Cell Fate Specification ◽

Fate Specification ◽

C Elegans ◽

Final Destination ◽

Multiple Cell

The migrations of cells and growth cones contribute to form and pattern during metazoan development. To study the mechanisms that regulate cell motility, we have screened for C. elegans mutants defective in the posteriorly directed migrations of the canal-associated neurons (CANs). Here we describe 14 genes necessary for CAN cell migration. Our characterization of the mutants has led to three conclusions. First, the mutations define three gene classes: genes necessary for cell fate specification, genes necessary for multiple cell migrations and a single gene necessary for final positioning of migrating cells. Second, cell interactions between the CAN and HSN, a neuron that migrates anteriorly to a position adjacent to the CAN, control the final destination of the HSN cell body. Third, C. elegans larval development requires the CANs. In the absence of CAN function, larvae arrest development, with excess fluid accumulating in their pseudocoeloms. This phenotype may reflect a role of the CANs in osmoregulation.

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DYC-1, a Protein Functionally Linked to Dystrophin in Caenorhabditis elegans Is Associated with the Dense Body, Where It Interacts with the Muscle LIM Domain Protein ZYX-1

Molecular Biology of the Cell ◽

10.1091/mbc.e07-05-0497 ◽

2008 ◽

Vol 19 (3) ◽

pp. 785-796 ◽

Cited By ~ 16

Author(s):

Claire Lecroisey ◽

Edwige Martin ◽

Marie-Christine Mariol ◽

Laure Granger ◽

Yannick Schwab ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Dense Body ◽

Striated Muscles ◽

Lim Domain ◽

Functional Link ◽

C Elegans ◽

Lim Domain Protein ◽

Muscle Necrosis ◽

Domain Protein

In Caenorhabditis elegans, mutations of the dystrophin homologue, dys-1, produce a peculiar behavioral phenotype (hyperactivity and a tendency to hypercontract). In a sensitized genetic background, dys-1 mutations also lead to muscle necrosis. The dyc-1 gene was previously identified in a genetic screen because its mutation leads to the same phenotype as dys-1, suggesting that the two genes are functionally linked. Here, we report the detailed characterization of the dyc-1 gene. dyc-1 encodes two isoforms, which are expressed in neurons and muscles. Isoform-specific RNAi experiments show that the absence of the muscle isoform, and not that of the neuronal isoform, is responsible for the dyc-1 mutant phenotype. In the sarcomere, the DYC-1 protein is localized at the edges of the dense body, the nematode muscle adhesion structure where actin filaments are anchored and linked to the sarcolemma. In yeast two-hybrid assays, DYC-1 interacts with ZYX-1, the homologue of the vertebrate focal adhesion LIM domain protein zyxin. ZYX-1 localizes at dense bodies and M-lines as well as in the nucleus of C. elegans striated muscles. The DYC-1 protein possesses a highly conserved 19 amino acid sequence, which is involved in the interaction with ZYX-1 and which is sufficient for addressing DYC-1 to the dense body. Altogether our findings indicate that DYC-1 may be involved in dense body function and stability. This, taken together with the functional link between the C. elegans DYC-1 and DYS-1 proteins, furthermore suggests a requirement of dystrophin function at this structure. As the dense body shares functional similarity with both the vertebrate Z-disk and the costamere, we therefore postulate that disruption of muscle cell adhesion structures might be the primary event of muscle degeneration occurring in the absence of dystrophin, in C. elegans as well as vertebrates.

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Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage

Biomolecules ◽

10.3390/biom10070993 ◽

2020 ◽

Vol 10 (7) ◽

pp. 993

Author(s):

Yuri Lee ◽

Hyeseon Jeong ◽

Kyung Hwan Park ◽

Kyung Won Kim

Keyword(s):

Caenorhabditis Elegans ◽

Therapeutic Strategy ◽

Axon Regeneration ◽

Neuronal Damage ◽

Biological Processes ◽

Nematode Caenorhabditis Elegans ◽

C Elegans ◽

Neuronal Functions ◽

Molecular Components

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD+ biosynthetic enzymes and NAD+-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode Caenorhabditis elegans has served as a model to study the neuronal role of NAD+ because many molecular components regulating NAD+ are highly conserved. This review focuses on recent findings using C. elegans models of neuronal damage pertaining to the neuronal functions of NAD+ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD+ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage.

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