The in vivo effect of actin cytoskeletal abnormalities on gene expression

Remodeling of the actin cytoskeleton through actin dynamics (assembly and disassembly of filamentous actin) is known to be essential for numerous basic biological processes. In addition, recent in vitro studies provided evidence that actin dynamics participate in the control of gene expression. A spontaneous mouse mutant, corneal disease 1 (corn1), is deficient for a regulator of actin dynamics, destrin (DSTN; also known as actin depolymerizing factor or ADF), and develops epithelial hyperproliferation and neovascularization in the cornea. Dstncorn1 mice exhibit the actin dynamics defect in the corneal epithelial cells as evidenced by increased filamentous actin, offering an in vivo model to investigate the physiological significance of the transcriptional regulation by actin dynamics. To examine the effect of the Dstncorn1 mutation on gene expression, we performed a microarray analysis using the cornea from Dstncorn1 and wild-type control mice. A dramatic alteration of gene expression was observed in the Dstncorn1 cornea, with 1,226 annotated genes differentially expressed. Functional annotation of these genes revealed that most significantly enriched functional categories are associated with actin and/or cytoskeleton. Among genes that belong to these categories, a considerable number of serum response factor (SRF) target genes were found, indicating the existence of the actin-SRF pathway of transcriptional regulation in vivo. A comparative study using an allelic mutant strain, Dstncorn1-2J, with milder corneal phenotypes also suggested that the severity of the actin dynamics defect correlates with the level of gene expression changes. Our study provides evidence that actin dynamics have a strong impact on gene expression in vivo.

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Verdoni AM, Aoyama N, Ikeda A, Ikeda S