Sensitivity of the brain transcriptome to connexin ablation

Abstract

Extensive studies on mice with total or partial disruption of either connexin43 (Cx43) or connexin32 (Cx32) have detected only subtle changes in central nervous system structure, growth, development, or function. We have used high density cDNA arrays to analyze the regulation, control, and coordination of the abundances of 7446 distinct transcripts in four brains, each of Cx43 null (K43), Cx43 heterozygous (H43), and Cx32 null (K32) mice as compared to the brains of wildtype (W) mice. The use of multiple samples allowed the determination of the statistical significance of gene regulation. Significantly regulated genes encoded proteins of all functional categories, extending beyond those that might be expected to depend on junctional communication. Moreover, we found a high degree of similarity between genes regulated in the K43 and H43 brains and a remarkable overlap between gene regulation in brains of K43 and K32. The regulated genes in both K43 and H43 brains showed an outstanding inverse coordination with the levels of expression of Cx43 in W brain, indicating that the regulated genes are largely predictable from their co-variance with Cx43 in the wildtype samples. These findings lead to the hypothesis that connexin expression may represent a central node in the regulation of gene expression patterns in brain.

Human oligodendrocytes express Cx31.3: Function and interactions with Cx32 mutants

“…Although these in vitro results may not fully reflect the in vivo situation, at least one Cx32 mutant associated with CNS findings (R142W) did not affect the localization of Cx29 in myelinating Schwann cells (Jeng et al 2006). However, a possibility not investigated in this study is that lack of one functional connexin gene could affect the expression of other genes in the CNS (Iacobas et al 2005). Through this mechanism Cx32 mutations could have indirect intracellular consequences on other connexins without necessarily directly impeding their function.…”

Mathematical model of morphogen electrophoresis through gap junctions

“…An important aspect is the identification of gene transcription modulated by the intracellular arrival of GJC-dependent morphogens into cells. Although these studies are just beginning in our laboratory in the context of the asymmetric gene cascade, others have begun to characterize, using transcriptome analysis, the genetic targets of gap junction-mediated signaling (Iacobas et al, 2003(Iacobas et al, , 2004(Iacobas et al, , 2005Kim et al, 2005). It is now abundantly clear that a large number of important gene networks are potentially controlled by GJC signaling and these networks represent excellent targets for future molecular dissection.…”

“…It is now abundantly clear that a large number of important gene networks are potentially controlled by GJC signaling and these networks represent excellent targets for future molecular dissection. For example, recent analysis links the expression of Syndecan-2 with connexin43 in mouse embryos (Iacobas et al, 2005), which is the first glimpse of conservation of regulatory circuits among the known roles of GJC and Syndecan-2 in lower vertebrates and mammals in establishment of left-right asymmetry Fukumoto and Levin, 2005). The model predicts that microarray analysis of Xenopus embryos receiving intracellular injections of serotonin on the ventral side will reveal genes up-and downregulated by this signal.…”

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…Gap junctional communication and Gap junction alpha-1 protein (GJA1) expression is affected in cerebral ischemia (Kielian and Esen, 2004) and in different stages of AD (Iacobas et al, 2005). Protein kinase C-induced ubiquitylation of GJA1 is partly mediated by the mitogen-activated protein kinase pathway (Leithe and Rivedal, 2004).…”