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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE37239 | GEO | 2012/04/14

SECONDARY ACCESSION(S): PRJNA159223

REPOSITORIES: GEO

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Project description:Microarray experiments have generally focused on magnitude of gene expression changes in pathological conditions, thereby using the method as a high throughput screen to identify candidate marker genes and/or to validate phenotypic differences. We have used novel strategies to extract additional information from array studies, including expression variability and coordination, from which organizational principles of transcriptomes are emerging. We have reported that expression level, variability and coordination of numerous genes are regulated in brains of Gja1-/- mice with respect to wildtypes. Moreover, expression coordination with Gja1 in wildtypes largely predicted expression regulation in Gja1-/- tissues. We now report a remarkable overlap between regulations in Gja1-/- and Gjb1-/- brains, and that both differ markedly from those in Gja9-/- brain. Since in brain these three connexins are expressed in different cell types (Gja1 in astrocytes, and ependymal and vascular cells, Gjb1 in oligodendrocytes, and Gja9 in neurons and microglia), and because astrocytes and oligodendrocytes may form syncytia coupled by gap junction channels, these observations suggest the existence of distinct connexin-dependent panglial and neuronal transcriptomic networks. Such networks, where linkage partners are rearranged and strengths modified in brains of knockouts, may explain downstream and parallel 'ripples' of phenotypic change resulting from single gene alterations as the composition and interactions of transcription factor networks in the wildtype brain were identified and found to be altered disruption of Gja1 or Gjb1. The transcription factors also formed network hubs with genes from other functional categories, thus allowing regulation of one functional pathway through manipulation of another. Keywords: genetic modification The brain transcriptomes of Gja9(-/-) and Gja9(+/-) P10 mice were compared to that of P10 wildtype mouse using the "multiple yellow" design in which extracts of biological replicas of the same genotype were hybridized with six 27k AECOM mouse cDNA microarrays (4 biological replicas of each genotype). These data were further compared to previously reported data on brain of neonatal wildtype, Gja1(-/-), Gja1(+/-) and Gjb1(-/-) mice (four biological replicas per genotype, reference sample design).

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

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