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1.
Genome Biol Evol ; 14(2)2022 02 04.
Article in English | MEDLINE | ID: mdl-35078241

ABSTRACT

About 10% of bacteria have a multichromosome genome with a primary replicon of bacterial origin, called the chromosome, and other replicons of plasmid origin, the chromids. Studies on multichromosome bacteria revealed potential points of coordination between the replication/segregation of chromids and the progression of the cell cycle. For example, replication of the chromid of Vibrionales (called Chr2) is initiated upon duplication of a sequence carried by the primary chromosome (called Chr1), in such a way that replication of both replicons is completed synchronously. Also, Chr2 uses the Chr1 as a scaffold for its partition in the daughter cells. How many of the features detected so far are required for the proper integration of a secondary chromosome in the cell cycle? How many more features remain to be discovered? We hypothesized that critical features for the integration of the replication/segregation of a given chromid within the cell cycle program would be conserved independently of the species in which the chromid has settled. Hence, we searched for a chromid related to that found in Vibrionales outside of this order. We identified one in Plesiomonas shigelloides, an aquatic and pathogenic enterobacterium that diverged early within the clade of Enterobacterales. Our results suggest that the chromids present in P. shigelloides and Vibrionales derive from a common ancestor. We initiated in silico genomic and proteomic comparative analyses of P. shigelloides, Vibrionales, and Enterobacterales that enabled us to establish a list of features likely involved in the maintenance of the chromid within the host cell cycle.


Subject(s)
Plesiomonas , Vibrio , Chromosomes, Bacterial/genetics , Genome, Bacterial , Plesiomonas/genetics , Proteomics , Vibrio/genetics
2.
Mol Cell ; 79(5): 857-869.e3, 2020 09 03.
Article in English | MEDLINE | ID: mdl-32681820

ABSTRACT

Sister-chromatid cohesion describes the orderly association of newly replicated DNA molecules behind replication forks. It plays an essential role in the maintenance and faithful transmission of genetic information. Cohesion is created by DNA topological links and proteinaceous bridges, whose formation and deposition could be potentially affected by many processes. Current knowledge on cohesion has been mainly gained by fluorescence microscopy observation. However, the resolution limit of microscopy and the restricted number of genomic positions that can be simultaneously visualized considerably hampered progress. Here, we present a high-throughput methodology to monitor sister-chromatid contacts (Hi-SC2). Using the multi-chromosomal Vibrio cholerae bacterium as a model, we show that Hi-SC2 permits to monitor local variations in sister-chromatid cohesion at a high resolution over a whole genome.


Subject(s)
Chromatids/physiology , Genetic Techniques , Vibrio cholerae/genetics , Chromosomes, Bacterial/physiology , DNA Replication , DNA, Bacterial , High-Throughput Nucleotide Sequencing , Integrases/metabolism , Nucleic Acid Conformation
3.
Proc Natl Acad Sci U S A ; 116(37): 18391-18396, 2019 09 10.
Article in English | MEDLINE | ID: mdl-31420511

ABSTRACT

The circular chromosomes of bacteria can be concatenated into dimers by homologous recombination. Dimers are solved by the addition of a cross-over at a specific chromosomal site, dif, by 2 related tyrosine recombinases, XerC and XerD. Each enzyme catalyzes the exchange of a specific pair of strands. Some plasmids exploit the Xer machinery for concatemer resolution. Other mobile elements exploit it to integrate into the genome of their host. Chromosome dimer resolution is initiated by XerD. The reaction is under the control of a cell-division protein, FtsK, which activates XerD by a direct contact. Most mobile elements exploit FtsK-independent Xer recombination reactions initiated by XerC. The only notable exception is the toxin-linked cryptic satellite phage of Vibrio cholerae, TLCΦ, which integrates into and excises from the dif site of the primary chromosome of its host by a reaction initiated by XerD. However, the reaction remains independent of FtsK. Here, we show that TLCΦ carries a Xer recombination activation factor, XafT. We demonstrate in vitro that XafT activates XerD catalysis. Correspondingly, we found that XafT specifically interacts with XerD. We further show that integrative mobile elements exploiting Xer (IMEXs) encoding a XafT-like protein are widespread in gamma- and beta-proteobacteria, including human, animal, and plant pathogens.


Subject(s)
Bacteriophages/genetics , Integrases/metabolism , Recombinases/metabolism , Recombination, Genetic , Vibrio cholerae/metabolism , Vibrio cholerae/virology , Bacterial Proteins/metabolism , Base Sequence , Cholera Toxin , Chromosomes, Bacterial/genetics , Escherichia coli/metabolism , Escherichia coli Proteins , Integrases/genetics , Membrane Proteins/genetics , Plasmids , Vibrio cholerae/genetics
4.
PLoS Genet ; 13(3): e1006702, 2017 03.
Article in English | MEDLINE | ID: mdl-28358835

ABSTRACT

Homologous recombination between the circular chromosomes of bacteria can generate chromosome dimers. They are resolved by a recombination event at a specific site in the replication terminus of chromosomes, dif, by dedicated tyrosine recombinases. The reaction is under the control of a cell division protein, FtsK, which assembles into active DNA pumps at mid-cell during septum formation. Previous studies suggested that activation of Xer recombination at dif was restricted to chromosome dimers in Escherichia coli but not in Vibrio cholerae, suggesting that FtsK mainly acted on chromosome dimers in E. coli but frequently processed monomeric chromosomes in V. cholerae. However, recent microscopic studies suggested that E. coli FtsK served to release the MatP-mediated cohesion and/or cell division apparatus-interaction of sister copies of the dif region independently of chromosome dimer formation. Here, we show that these apparently paradoxical observations are not linked to any difference in the dimer resolution machineries of E. coli and V. cholerae but to differences in the timing of segregation of their chromosomes. V. cholerae harbours two circular chromosomes, chr1 and chr2. We found that whatever the growth conditions, sister copies of the V. cholerae chr1 dif region remain together at mid-cell until the onset of constriction, which permits their processing by FtsK and the activation of dif-recombination. Likewise, sister copies of the dif region of the E. coli chromosome only separate after the onset of constriction in slow growth conditions. However, under fast growth conditions the dif sites separate before constriction, which restricts XerCD-dif activity to resolving chromosome dimers.


Subject(s)
Chromosomes, Bacterial/genetics , Escherichia coli Proteins/genetics , Escherichia coli/genetics , Homologous Recombination/genetics , Membrane Proteins/genetics , Cell Cycle/genetics , Cell Division/genetics , Chromosomal Proteins, Non-Histone/genetics , DNA, Circular/genetics , Escherichia coli/growth & development , Integrases/genetics , Optical Imaging , Recombinases/genetics , Vibrio cholerae/genetics , Vibrio cholerae/growth & development
5.
Sci Rep ; 7: 44505, 2017 03 16.
Article in English | MEDLINE | ID: mdl-28300142

ABSTRACT

Bacterial cell division is a highly regulated process, which involves the formation of a complex apparatus, the divisome, by over a dozen proteins. In the few model bacteria in which the division process was detailed, divisome assembly occurs in two distinct steps: a few proteins, including the FtsZ tubulin-like protein, form a membrane associated contractile ring, the Z-ring, at ~30% of the cell cycle. The Z-ring serves as a scaffold for the recruitment of a second series of proteins, including integral membrane and periplasmic cell wall remodelling enzymes, at ~50% of the cell cycle. Actual septation occupies most of the remaining half of the cell cycle. In contrast, we present evidence suggesting that early pre-divisional Z-rings form between 40 and 50% of the cell cycle and mature into fully assembled divisome at about 80% of the cell cycle in Vibrio cholerae. Thus, actual septation is restricted to a very short amount of time. Our results further suggest that late assembly of the divisome probably helps maintain the asymmetric polar organisation of V. cholerae cells by limiting the accumulation of a cell pole marker, HubP, at the nascent cell poles.


Subject(s)
Bacterial Proteins/chemistry , Cell Division/genetics , Cytokinesis/genetics , Cytoskeletal Proteins/chemistry , Vibrio cholerae/genetics , Bacterial Proteins/genetics , Bacterial Proteins/isolation & purification , Cell Cycle/genetics , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/genetics , Cell Wall/chemistry , Cell Wall/genetics , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/isolation & purification , Vibrio cholerae/chemistry , Vibrio cholerae/pathogenicity
6.
Nat Microbiol ; 1(9): 16094, 2016 Jun 27.
Article in English | MEDLINE | ID: mdl-27562255

ABSTRACT

Cell division must be coordinated with chromosome replication and segregation to ensure the faithful transmission of genetic information during proliferation. In most bacteria, assembly of the division apparatus, the divisome, starts with the polymerization of a tubulin homologue, FtsZ, into a ring-like structure at mid-cell, the Z-ring(1). It typically occurs at half of the cell cycle when most of the replication and segregation cycle of the unique chromosome they generally harbour is achieved(2). The chromosome itself participates in the regulation of cell division, at least in part because it serves as a scaffold to position FtsZ polymerization antagonists(3). However, about 10% of bacteria have more than one chromosome(4), which raises questions about the way they license cell division(3). For instance, the genome of Vibrio cholerae, the agent of cholera, is divided between a 3 Mbp replicon that originates from the chromosome of its mono-chromosomal ancestor, Chr1, and a 1 Mbp plasmid-derived replicon, Chr2 (ref. 5). Here, we show that Chr2 harbours binding motifs for an inhibitor of Z-ring formation, which helps accurately position the V. cholerae divisome at mid-cell and postpones its assembly to the very end of the cell cycle.


Subject(s)
Bacterial Proteins/metabolism , Cell Division/genetics , Cholera/microbiology , Chromosomes, Bacterial/genetics , Cytoskeletal Proteins/metabolism , Genome, Bacterial/genetics , Vibrio cholerae/genetics , Bacterial Proteins/genetics , Chromosome Segregation/genetics , Cytoskeletal Proteins/genetics , DNA Replication Timing , Plasmids/genetics , Vibrio cholerae/cytology , Vibrio cholerae/physiology
7.
PLoS Genet ; 11(5): e1005256, 2015 May.
Article in English | MEDLINE | ID: mdl-25992634

ABSTRACT

The Vibrio cholerae bacterium is the agent of cholera. The capacity to produce the cholera toxin, which is responsible for the deadly diarrhea associated with cholera epidemics, is encoded in the genome of a filamentous phage, CTXφ. Rolling-circle replication (RCR) is central to the life cycle of CTXφ because amplification of the phage genome permits its efficient integration into the genome and its packaging into new viral particles. A single phage-encoded HUH endonuclease initiates RCR of the proto-typical filamentous phages of enterobacteriaceae by introducing a nick at a specific position of the double stranded DNA form of the phage genome. The rest of the process is driven by host factors that are either essential or crucial for the replication of the host genome, such as the Rep SF1 helicase. In contrast, we show here that the histone-like HU protein of V. cholerae is necessary for the introduction of a nick by the HUH endonuclease of CTXφ. We further show that CTXφ RCR depends on a SF1 helicase normally implicated in DNA repair, UvrD, rather than Rep. In addition to CTXφ, we show that VGJφ, a representative member of a second family of vibrio integrative filamentous phages, requires UvrD and HU for RCR while TLCφ, a satellite phage, depends on Rep and is independent from HU.


Subject(s)
Bacterial Proteins/metabolism , DNA Helicases/metabolism , DNA-Binding Proteins/metabolism , Inovirus/genetics , Virus Replication , Bacterial Proteins/genetics , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Gene Deletion , Genome, Viral , Inovirus/physiology , Vibrio cholerae/enzymology , Vibrio cholerae/virology
8.
Proc Natl Acad Sci U S A ; 111(47): 16848-53, 2014 Nov 25.
Article in English | MEDLINE | ID: mdl-25385643

ABSTRACT

As in most bacteria, topological problems arising from the circularity of the two Vibrio cholerae chromosomes, chrI and chrII, are resolved by the addition of a crossover at a specific site of each chromosome, dif, by two tyrosine recombinases, XerC and XerD. The reaction is under the control of a cell division protein, FtsK, which activates the formation of a Holliday Junction (HJ) intermediate by XerD catalysis that is resolved into product by XerC catalysis. Many plasmids and phages exploit Xer recombination for dimer resolution and for integration, respectively. In all cases so far described, they rely on an alternative recombination pathway in which XerC catalyzes the formation of a HJ independently of FtsK. This is notably the case for CTXϕ, the cholera toxin phage. Here, we show that in contrast, integration of TLCϕ, a toxin-linked cryptic satellite phage that is almost always found integrated at the chrI dif site before CTXϕ, depends on the formation of a HJ by XerD catalysis, which is then resolved by XerC catalysis. The reaction nevertheless escapes the normal cellular control exerted by FtsK on XerD. In addition, we show that the same reaction promotes the excision of TLCϕ, along with any CTXϕ copy present between dif and its left attachment site, providing a plausible mechanism for how chrI CTXϕ copies can be eliminated, as occurred in the second wave of the current cholera pandemic.


Subject(s)
Bacterial Proteins/physiology , Bacteriophages/physiology , Genome, Bacterial , Vibrio cholerae/genetics , Virus Integration , Biocatalysis , Electrophoretic Mobility Shift Assay , Vibrio cholerae/virology
9.
PLoS Genet ; 10(9): e1004557, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25255436

ABSTRACT

The replication terminus region (Ter) of the unique chromosome of most bacteria locates at mid-cell at the time of cell division. In several species, this localization participates in the necessary coordination between chromosome segregation and cell division, notably for the selection of the division site, the licensing of the division machinery assembly and the correct alignment of chromosome dimer resolution sites. The genome of Vibrio cholerae, the agent of the deadly human disease cholera, is divided into two chromosomes, chrI and chrII. Previous fluorescent microscopy observations suggested that although the Ter regions of chrI and chrII replicate at the same time, chrII sister termini separated before cell division whereas chrI sister termini were maintained together at mid-cell, which raised questions on the management of the two chromosomes during cell division. Here, we simultaneously visualized the location of the dimer resolution locus of each of the two chromosomes. Our results confirm the late and early separation of chrI and chrII Ter sisters, respectively. They further suggest that the MatP/matS macrodomain organization system specifically delays chrI Ter sister separation. However, TerI loci remain in the vicinity of the cell centre in the absence of MatP and a genetic assay specifically designed to monitor the relative frequency of sister chromatid contacts during constriction suggest that they keep colliding together until the very end of cell division. In contrast, we found that even though it is not able to impede the separation of chrII Ter sisters before septation, the MatP/matS macrodomain organization system restricts their movement within the cell and permits their frequent interaction during septum constriction.


Subject(s)
Cell Division , Chromosomes, Bacterial , DNA Replication , Vibrio cholerae/physiology , Bacterial Proteins/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Chromosome Segregation , Recombination, Genetic , Sister Chromatid Exchange , Time-Lapse Imaging
10.
PLoS Genet ; 10(7): e1004448, 2014 Jul.
Article in English | MEDLINE | ID: mdl-25010199

ABSTRACT

The segregation of bacterial chromosomes follows a precise choreography of spatial organisation. It is initiated by the bipolar migration of the sister copies of the replication origin (ori). Most bacterial chromosomes contain a partition system (Par) with parS sites in close proximity to ori that contribute to the active mobilisation of the ori region towards the old pole. This is thought to result in a longitudinal chromosomal arrangement within the cell. In this study, we followed the duplication frequency and the cellular position of 19 Vibrio cholerae genome loci as a function of cell length. The genome of V. cholerae is divided between two chromosomes, chromosome I and II, which both contain a Par system. The ori region of chromosome I (oriI) is tethered to the old pole, whereas the ori region of chromosome II is found at midcell. Nevertheless, we found that both chromosomes adopted a longitudinal organisation. Chromosome I extended over the entire cell while chromosome II extended over the younger cell half. We further demonstrate that displacing parS sites away from the oriI region rotates the bulk of chromosome I. The only exception was the region where replication terminates, which still localised to the septum. However, the longitudinal arrangement of chromosome I persisted in Par mutants and, as was reported earlier, the ori region still localised towards the old pole. Finally, we show that the Par-independent longitudinal organisation and oriI polarity were perturbed by the introduction of a second origin. Taken together, these results suggest that the Par system is the major contributor to the longitudinal organisation of chromosome I but that the replication program also influences the arrangement of bacterial chromosomes.


Subject(s)
Chromosomes, Bacterial , DNA Replication/genetics , Origin Recognition Complex/genetics , Vibrio cholerae/genetics , Chromosome Segregation/genetics
11.
Neurobiol Dis ; 63: 92-106, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24291518

ABSTRACT

PCP4/PEP19 is a modulator of Ca(2+)-CaM signaling. In the brain, it is expressed in a very specific pattern in postmitotic neurons. In particular, Pcp4 is highly expressed in the Purkinje cell, the sole output neuron of the cerebellum. PCP4, located on human chromosome 21, is present in three copies in individuals with Down syndrome (DS). In a previous study using a transgenic mouse model (TgPCP4) to evaluate the consequences of 3 copies of this gene, we found that PCP4 overexpression induces precocious neuronal differentiation during mouse embryogenesis. Here, we report combined analyses of the cerebellum at postnatal stages (P14 and adult) in which we identified age-related molecular, electrophysiological, and behavioral alterations in the TgPCP4 mouse. While Pcp4 overexpression at P14 induces an earlier neuronal maturation, at adult stage it induces increase in cerebellar CaMK2alpha and in cerebellar LTD, as well as learning impairments. We therefore propose that PCP4 contributes significantly to the development of Down syndrome phenotypes through molecular and functional changes.


Subject(s)
Cerebellum/growth & development , Cerebellum/metabolism , Gene Expression Regulation, Developmental/physiology , Nerve Tissue Proteins/metabolism , Animals , Animals, Newborn , Cerebellum/cytology , Excitatory Amino Acid Antagonists/pharmacology , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/genetics , Humans , In Vitro Techniques , Long-Term Synaptic Depression/drug effects , Long-Term Synaptic Depression/genetics , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Motor Activity/drug effects , Motor Activity/genetics , Nerve Tissue Proteins/genetics , Neurons/drug effects , Neurons/physiology , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Quinoxalines/pharmacology , Reaction Time/drug effects , Reaction Time/genetics , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Sodium Channel Blockers/pharmacology , Tetrodotoxin/pharmacology , Valine/analogs & derivatives , Valine/pharmacology
12.
PLoS One ; 7(8): e41616, 2012.
Article in English | MEDLINE | ID: mdl-22912673

ABSTRACT

Forty percent of people with Down syndrome exhibit heart defects, most often an atrioventricular septal defect (AVSD) and less frequently a ventricular septal defect (VSD) or atrial septal defect (ASD). Lymphoblastoid cell lines (LCLs) were established from lymphocytes of individuals with trisomy 21, the chromosomal abnormality causing Down syndrome. Gene expression profiles generated from DNA microarrays of LCLs from individuals without heart defects (CHD(-); n = 22) were compared with those of LCLs from patients with cardiac malformations (CHD(+); n = 21). After quantile normalization, principal component analysis revealed that AVSD carriers could be distinguished from a combined group of ASD or VSD (ASD+VSD) carriers. From 9,758 expressed genes, we identified 889 and 1,016 genes differentially expressed between CHD(-) and AVSD and CHD(-) and ASD+VSD, respectively, with only 119 genes in common. A specific chromosomal enrichment was found in each group of affected genes. Among the differentially expressed genes, more than 65% are expressed in human or mouse fetal heart tissues (GEO dataset). Additional LCLs from new groups of AVSD and ASD+VSD patients were analyzed by quantitative PCR; observed expression ratios were similar to microarray results. Analysis of GO categories revealed enrichment of genes from pathways regulating clathrin-mediated endocytosis in patients with AVSD and of genes involved in semaphorin-plexin-driven cardiogenesis and the formation of cytoplasmic microtubules in patients with ASD-VSD. A pathway-oriented search revealed enrichment in the ciliome for both groups and a specific enrichment in Hedgehog and Jak-stat pathways among ASD+VSD patients. These genes or related pathways are therefore potentially involved in normal cardiogenesis as well as in cardiac malformations observed in individuals with trisomy 21.


Subject(s)
Down Syndrome/complications , Down Syndrome/pathology , Heart Septal Defects, Ventricular/complications , Heart Septal Defects/complications , Hedgehog Proteins/metabolism , Lymphocytes/pathology , Signal Transduction , Animals , Cell Line , Chromosomes, Human/genetics , Heart Septal Defects/genetics , Heart Septal Defects/metabolism , Heart Septal Defects/pathology , Heart Septal Defects, Ventricular/genetics , Heart Septal Defects, Ventricular/metabolism , Heart Septal Defects, Ventricular/pathology , Humans , Mice , Phenotype , Transcriptome , Young Adult
13.
PLoS One ; 7(1): e29056, 2012.
Article in English | MEDLINE | ID: mdl-22253703

ABSTRACT

BACKGROUND: The cystathionine ß-synthase (CBS) gene, located on human chromosome 21q22.3, is a good candidate for playing a role in the Down Syndrome (DS) cognitive profile: it is overexpressed in the brain of individuals with DS, and it encodes a key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have studied the neural consequences of CBS overexpression in a transgenic mouse line (60.4P102D1) expressing the human CBS gene under the control of its endogenous regulatory regions. These mice displayed a ∼2-fold increase in total CBS proteins in different brain areas and a ∼1.3-fold increase in CBS activity in the cerebellum and the hippocampus. No major disturbance of SAA metabolism was observed, and the transgenic mice showed normal behavior in the rotarod and passive avoidance tests. However, we found that hippocampal synaptic plasticity is facilitated in the 60.4P102D1 line. CONCLUSION/SIGNIFICANCE: We demonstrate that CBS overexpression has functional consequences on hippocampal neuronal networks. These results shed new light on the function of the CBS gene, and raise the interesting possibility that CBS overexpression might have an advantageous effect on some cognitive functions in DS.


Subject(s)
Brain/physiology , Cystathionine beta-Synthase/metabolism , Amino Acids, Sulfur/metabolism , Animals , Behavior, Animal/physiology , Blotting, Western , Gene Dosage , Humans , Long-Term Potentiation/physiology , Metabolic Networks and Pathways , Metabolome , Mice , Mice, Transgenic , Organ Specificity , Phenotype , Synapses/metabolism , Synaptic Transmission/physiology , Transgenes/genetics
14.
PLoS One ; 4(2): e4606, 2009.
Article in English | MEDLINE | ID: mdl-19242551

ABSTRACT

Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) - a member of a natural polyphenols family, found in great amount in green tea leaves - is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice.


Subject(s)
Catechin/analogs & derivatives , Flavonoids/pharmacology , Phenols/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Animals , Antioxidants/pharmacology , Brain/growth & development , Catechin/pharmacology , Gene Dosage , Humans , Memory , Mice , Mice, Transgenic , Neuronal Plasticity , Polyphenols , Protein Serine-Threonine Kinases/physiology , Protein-Tyrosine Kinases/physiology , Tea , Dyrk Kinases
15.
Biochem Biophys Res Commun ; 346(4): 1303-6, 2006 Aug 11.
Article in English | MEDLINE | ID: mdl-16806076

ABSTRACT

Patients with Down syndrome appear to be protected from the development of atherosclerosis. On the contrary, hyperhomocysteinemia is associated with an increased risk for atherosclerosis. As hyperhomocysteinemia due to cystathionine beta synthase deficiency is associated with a decreased expression of paraoxonase-1, a major anti-atherosclerotic component secreted by the liver, we aimed to analyze the expression of paraoxonase-1 and cystathionine beta synthase in Down syndrome fetal liver by quantitative real-time reverse transcriptase-polymerase chain reaction. Paraoxonase-1 was up-regulated in Down syndrome fetal liver, while cystathionine beta synthase gene expression in Down syndrome fetuses was similar to the gene level in control fetuses. Moreover, there was no evidence for an association between paraoxonase-1 genotypes influencing paraoxonase-1 gene expression and Down syndrome. Since most serum paraoxonase-1 is synthesized in the liver, an increase of hepatic paraoxonase-1 expression might be one of the factors which could explain the low incidence of atherosclerotic vascular disease in Down syndrome.


Subject(s)
Aryldialkylphosphatase/metabolism , Down Syndrome/metabolism , Gene Expression/physiology , Aryldialkylphosphatase/genetics , Fetus/anatomy & histology , Humans , Liver/metabolism , Up-Regulation
16.
Free Radic Biol Med ; 40(11): 1971-80, 2006 Jun 01.
Article in English | MEDLINE | ID: mdl-16716898

ABSTRACT

Previous studies have shown that transgenic mice overexpressing Cu/Zn superoxide dismutase, a model of Down syndrome, exhibit premature thymic involution. We have performed a flow cytometry analysis of the developing thymus in these homozygous transgenic mice (hSOD1/hSOD1: Tg-SOD). Longitudinal follow-up analysis from day 3 to day 280 showed an early thymic development in Tg-SOD mice compared with controls. This early thymic development was associated with an increased migration of mature T cells to peripheral lymphoid organs. BrdU labeling showed no difference between Tg-SOD and control mice, confirming that the greater number of peripheral T cells in Tg-SOD mice was not due to extensive proliferation of these cells but rather to a greater pool of emigrant T cells in Tg-SOD.


Subject(s)
Down Syndrome/pathology , Superoxide Dismutase/genetics , T-Lymphocytes/cytology , Thymus Gland/pathology , Animals , Cell Differentiation , Disease Models, Animal , Down Syndrome/enzymology , Humans , Longitudinal Studies , Mice , Mice, Transgenic
17.
Int J Dev Neurosci ; 23(5): 475-84, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15946822

ABSTRACT

Human SIM2 is the ortholog of Drosophila single-minded (sim), a master regulator of neurogenesis and transcriptional factor controlling midline cell fate determination. We previously localized SIM2 in a chromosome 21 critical region for Down syndrome (DS). Here, we studied SIM2 gene using a new approach to provide insights in understanding of its potential role in human development. For the first time, we showed SIM2 spatial and temporal expression pattern during human central nervous system (CNS) development, from embryonic to fetal stages. Additional investigations were performed using a new optic microscopy technology to compare signal intensity and cell density [M. Rachidi, C. Lopes, S. Gassanova, P.M. Sinet, M. Vekemans, T. Attie, A.L. Delezoide, J.M. Delabar, Regional and cellular specificity of the expression of TPRD, the tetratricopeptide Down syndrome gene, during human embryonic development, Mech. Dev. 93 (2000) 189--193]. In embryonic stages, SIM2 was identified predominantly in restricted regions of CNS, in ventral part of D1/D2 diencephalic neuroepithelium, along the neural tube and in a few cell subsets of dorsal root ganglia. In fetal stages, SIM2 showed differential expression in pyramidal and granular cell layers of hippocampal formation, in cortical cells and in cerebellar external granular and Purkinje cell layers. SIM2 expression in embryonic and fetal brain could suggest a potential role in human CNS development, in agreement with Drosophila and mouse Sim mutant phenotypes and with the conservation of the Sim function in CNS development from Drosophila to Human. SIM2 expression in human fetal brain regions, which correspond to key structures for cognitive processes, correlates well with the behavioral phenotypes of Drosophila Sim mutants and transgenic mice overexpressing Sim2. In addition, SIM2-expressing brain regions correspond to the altered structures in DS patients. All together, these findings suggest a potential role of SIM2 in CNS development and indicate that SIM2 overexpression could participate to the pathogenesis of mental retardation in Down syndrome patients.


Subject(s)
Brain/embryology , Down Syndrome/embryology , Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors , Embryo, Mammalian/metabolism , Fetus/metabolism , Gestational Age , Humans , Time Factors , Tissue Distribution
18.
FEBS Lett ; 579(17): 3613-8, 2005 Jul 04.
Article in English | MEDLINE | ID: mdl-15961078

ABSTRACT

Premature ageing, one of the characteristics of Down syndrome (DS), may involve oxidative stress and impairment of proteasome activity. Transgenic mice overexpressing the human copper/zinc superoxide dismutase (SOD1) gene are one of the first murine models for DS and it has been shown that SOD1 overexpression might be either deleterious or beneficial. Here, we show a reduction in proteasome activities in the cortex of SOD1 transgenic mice and an associated increase in the content of oxidized SOD1 protein. As we demonstrate that in vitro oxidized SOD can inhibit purified proteasome peptidase activities, modified SOD1 might be partially responsible for proteasome inhibition shown in SOD1 transgenic mice.


Subject(s)
Cerebral Cortex/enzymology , Down Syndrome/enzymology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors , Superoxide Dismutase/metabolism , Animals , Down Syndrome/genetics , Humans , Mice , Mice, Transgenic , Oxidation-Reduction , Proteasome Endopeptidase Complex/analysis , Superoxide Dismutase/genetics , Superoxide Dismutase-1 , Transcriptional Activation
19.
J Neurochem ; 89(1): 33-43, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15030387

ABSTRACT

Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine concentrations and causes hyperhomocysteinemia, a common risk factor for vascular disease, stroke and possibly neurodegenerative diseases. Various neuronal diseases have been associated with hyperhomocysteinemia, but the molecular mechanisms of homocysteine toxicity are unknown. We investigated the pathways involved in the pathological process, by analyzing differential gene expression in neuronal tissues. We used a combination of differential display and cDNA arrays to identify genes differentially expressed during hyperhomocysteinemia in brain of CBS-deficient mice. In this murine model of hyperhomocysteinemia, both plasma and brain homocysteine concentrations were high. Several genes were found to be differentially expressed in the brains of CBS-deficient mice, and the identities of some of these genes suggested that the SAPK/JNK pathway was altered in the brains of CBS-deficient mice. We therefore investigated the activation of proteins involved in the SAPK/JNK cascade. JNK and c-Jun were activated in the hippocampal neurones of CBS-deficient mice, suggesting that the SAPK/JNK pathway may play an important role in the development of neuronal defects associated with hyperhomocysteinemia.


Subject(s)
Brain/metabolism , Hyperhomocysteinemia/metabolism , MAP Kinase Kinase 4 , Neurons/metabolism , Signal Transduction/physiology , Activating Transcription Factor 2 , Animals , Brain/cytology , Brain Chemistry , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Cystathionine beta-Synthase/deficiency , Cystathionine beta-Synthase/genetics , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation , Hippocampus/cytology , Hippocampus/metabolism , Homocysteine/blood , Homocysteine/metabolism , Hyperhomocysteinemia/genetics , JNK Mitogen-Activated Protein Kinases , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase Kinases/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , Oligonucleotide Array Sequence Analysis , Signal Transduction/genetics , Transcription Factors/genetics , Transcription Factors/metabolism
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