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Gap junction and purinergic P2 receptor proteins as a functional unit: insights from transcriptomics

ABSTRACT: Gap junctions and purinergic P2 receptors (P2Rs) can be regarded as belonging to a common functional unit, given that they are involved in the transmission of calcium signals between cells. We have previously shown that deletion of the Gja1 gene alters expression levels of numerous genes encoding proteins with diverse functions, including purinergic, P2Rs, and have found that genes synergistically or antagonistically expressed in wildtype tissues are more prone to be similarly or oppositely regulated in Cx43-nulls. We have now explored the use of coordination analysis of gene expression as a strategy to identify interlinked genes encoding functionally related proteins and used pull-downs to evaluate their interlinkage. Our findings indicate that, in brain and in cultured astrocytes, several of these co-expressed genes encode proteins that are components of P2R signal transduction pathways and/or directly interact with these receptors, including the gap junction protein connexin43 (Cx43) and connexin45 (Cx45), as well as pannexins. It is proposed that coordination analysis of gene expression may provide a novel unbiased strategy for the identification of proteins belonging to supramolecular complexes. Keywords: genetic modification

ORGANISM(S): Mus musculus

PROVIDER: GSE8105 | GEO | 2007/06/20

SECONDARY ACCESSION(S): PRJNA100967

REPOSITORIES: GEO

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The connexin43-dependent transcriptome during brain development: importance of genetic background

Project description:Use of null mutant mice is a powerful way to evaluate the role of specific proteins in brain function. Studies performed on knockout mice have revealed some unexpected roles of the gap junction proteins (the connexins). Thus, analyses of gene expression in connexin43 (Cx43) null brains indicated that deletion of a single gene (Gja1) induced expression level change of numerous other genes located on all chromosomes and involved in a wide diversity of functional pathways. The significant overlap between alterations in gene expression level, control and coordination in Cx43 knockout and knockdown astrocytes raised the possibility that Gja1 represents a transcriptomic node of gene regulatory networks. However, conditional deletion of Gja1 in astrocytes of two mouse strains resulted in remarkably different phenotypes. In order to evaluate the influence of the genetic background on the transcriptome, we performed microarray studies on brains of GFAP-Cre:Cx43f/f C57Bl/6 and 129/SVEV mice. The surprisingly low number of Cx43 core genes (regulated in all Cx43 nulls regardless of strain) and the high number of differently regulated genes in the two Cx43 CKOs indicate high influence of mouse strain on brain transcriptome. The transcriptomes of WT and Cx43 null brains from both C57Bl/6 and SVEV strains were profiled and compared at perinatal and adult time points to learn more about the strain dependence of the Cx43-null phenotype. For this purpose, differently labeled cDNAs from biological replicas (4 of each genotype) were co-hybridized with Duke MO36K mouse oligonucleotide array spotted with 36k Operon oligonucleotides V4.0.

2012-04-13 | E-GEOD-37239 | biostudies-arrayexpress

The connexin43-dependent transcriptome during brain development: importance of genetic background

2012-04-14 | GSE37239 | GEO

Secretome analysis of Cx43 expressing cells

Project description:Extracellular matrix remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes within the extracellular environment that are specific to GBM cell motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the conditioned media of Cx43-expressing C6 rat glioma cells was found to increase the motility of the parental line. Demonstrating the selective engagement of ECM-remodelling pathways, secretome analysis revealed the near-binary expression of osteopontin and matrix metalloproteinase-3 (MMP3).

2019-04-17 | PXD012175 | Pride

Mus musculus

Project description:Gap junction and purinergic P2 receptor proteins as a functional unit: insights from transcriptomics

| PRJNA100967 | ENA

“Compensatory” transcriptional mechanisms: Comparison of transcriptomes of Cx43 null and knockdown astrocytes

Project description:Our previous studies on brains and hearts of Cx null mice have revealed that expression level, control and coordination of a very large number of genes are regulated compared to wildtype littermates. This result suggests the possibility that the phenotype of the Cx null animals may include genes not only linked to the intracellular communication that gap junction channels provide but also to genes with very different functions. The question often arises, however, of the degree to which “compensation” occurs in knockouts such that gene regulation depends on pathways altered to make up for the missing gene rather than reflecting normal gene interlinkage. In order to explore this question in the Cx43 null setting, we have compared gene expression patterns in Cx43 null astrocytes with that in wildtype astrocytes acutely treated (36 hrs) with Cx43 siRNA. In these studies, Cx43 levels determined by Western blot analysis were reduced by at least 70% following siRNA treatment, comparable with the 3.24x downregulation for mRNA. For each group of astrocytes, four independent cultures were compared, using oligonucleotide microarrays printed with the mouse Qiagen library. 8060 well annotated unigenes were identifiable in all 8 arrays; of these, 8.2% were upregulated and 6.0% downregulated in Cx43 null astrocytes and 6.2% upreguated and 7.0 downregulated in siRNA treated astrocytes. Interestingly, regulation of 92.3% unigenes significantly regulated in both Cx43 deficient astrocytes had the same orientation, representing a highly significant overlap of gene expression alteration. These experiments thus indicate that the gene regulation in Cx43 null astrocytes is largely due to direct interlinkage rather than to developmental compensation for the missing gene. Keywords: genetic modification

2007-06-20 | GSE8168 | GEO

Gray but not white matter astroglia-specific connexin 43 ablation ameliorates neuroinflammation [Agilent]

Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.

2021-04-20 | GSE148929 | GEO

Gray but not white matter astroglia-specific connexin 43 ablation ameliorates neuroinflammation [Affymetrix]

2021-04-20 | GSE148931 | GEO

Bulk RNA-sequencing of murine atrioventricular nodes

Project description:Tissue-resident macrophages abound in the distal atrioventricular (AV) node of the heart, electrically couple to conducting cardiomyocytes via Connexin (Cx) 43-containing gap junctions and are implicated in normal and aberrant cardiac conduction. Moreover, conditional deletion of Cx43 in macrophages (tamoxifen-inducible Cx3cr1 Cx43-/- mice) delays AV conduction and acute depletion of macrophages in Cd11bDTR mice induces progressive AV block.

2017-04-20 | GSE86306 | GEO

Primary Osteocyte Supernatants Metabolomic Profiling of Two Transgenic Mice with Connexin43 Dominant Negative Mutants

Project description:<p>Osteocytes could release some small molecules (≤ 1 kDa) through gap junctions and hemichannels to extracellular environment, such as prostaglandin E2 (PGE2), nitric oxide (NO) and adenosine triphosphate (ATP), which play key roles in transferring signals between bone cells and other tissue cells. Connexin (Cx) 43 is the most abundant connexin in osteocytes. To further discover molecules released by osteocytes through Cx43 channels and better understand the regulatory function of Cx43 channels in osteocytes, we performed non-targeted global metabolomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) on conditioned medium collected from osteocytes isolated from two transgenic mouse models with Cx43 dominant negative mutants driven by a 10 kb-DMP1 promoter: R76W (gap junctions are blocked, whereas hemichannels are promoted) and Δ130-136 (both gap junctions and hemichannels are blocked). The results revealed that several new categories of molecules, such as “fatty acyls” and “carboxylic acids and derivatives”, could be released through osteocytic Cx43 channels. In addition, alteration of Cx43 channel function affected the release of metabolites related to inflammatory reaction and oxidative stress. Pathway analysis further showed that citric acid cycle was the most differential metabolic pathway regulated by Cx43 channels. In sum, these results isolated new potential metabolites released by osteocytes through Cx43 channels, and offered a novel perspective to understand the regulatory mechanisms of osteocytes on themselves and other cells as well.</p>

2021-04-14 | MTBLS2358 | MetaboLights

ATO treatment on mesenchymal stem cells (MSCs) interacting breast cancer cells

Project description:Based on next generation RNA-seq, we examed Arsenic trioxide treatment (ATO) effect on MSCs-interacting MCF7 cells in 3D cultures. We found gap junction protein Cx43 is dramatically downregulated after ATO treatment..

2018-10-01 | GSE118923 | GEO

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