Involvement of SOX proteins in lens-specific activation of crystallin genes

Abstract

We have studied the mechanism of δ1-crystallin gene activation, which occurs early in lens cell differentiation, and have previously shown that an essential element of the δ1-crystallin enhancer is bound by a group of nuclear factors, δEF2, among which δEF2a is highly enriched in lens cells. In this report we show that the cDNA of δEF2a codes for the chicken SOX-2 protein (cSOX-2), which is structurally related to the sex-determining factor SRY. Sox-2 is expressed at high levels in the early developing lens in both chicken and mouse embryos. Overexpression of δEF2a/cSOX-2 increased δ1-crystallin enhancer activity to a plateau in lens cells, but not in fibroblasts, consistent with the previously drawn conclusion that δEF2a activates transcription only in concert with another factor present in the lens. This result supports the model that SOX proteins act as architectural components in the activating complex formed on an enhancer, as indicated for another HXG domain protein, lymphoid enhancer binding factor 1 (LEF-1). We also show that SOX protein binding is essential for lens-specific promoter activity of the mouse γF-crystallin gene. This work is the first to show δ- and γ-crystallin genes as examples of direct regulatory targets of SOX proteins and provides evidence that diversified crystallin genes are regulated, at least partly, by a common mechanism.