Connexin-dependent transcellular transcriptomic networks in mouse brain

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 the expression level, variability and coordination of numerous genes are regulated in brains of connexin43 null (Gja1(-/-)) mouse with respect to wildtype. Moreover, expression coordination with Gja1 in wildtype largely predicted the expression regulation in Gja1(-/-) tissues. We now report a remarkable overlap between regulations in Gja1(-/-) and connexin32 null (Gjb1(-/-)) brains, and that both differ markedly from those in connexin36 null (Gja9(-/-)) brain. Since in brain these three connexins are expressed in different cell types (Cx43 in astrocytes, ependymal and vascular cells, Gjb1 in oligodendrocytes, and Cx36 in neurons and microglia), and because astrocytes and oligodendrocytes (and possibly neurons and microglia) 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 manipulations as illustrated by alterations in transcription factor networks resulting from deletion 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.