Persistent FoxE3 expression blocks cytoskeletal remodeling and organelle degradation during lens fiber differentiation.

PURPOSE The anterior hemisphere of the lens is covered by an epithelial monolayer that acts as the stem cell population for lens fiber progenitors. Foxe3, a forkhead transcription factor, is essential for proliferation and survival of the epithelial cells, and cessation of Foxe3 expression at the lens equator coincides with the cell cycle arrest that marks initiation of fiber differentiation. In this study, the consequences of persistent Foxe3 expression during fiber differentiation was investigated. METHODS The alpha-A-crystallin (Cryaa) promoter was used to drive transgenic expression of Foxe3 in murine differentiating lens fibers. RESULTS Transgenic mice have a dramatically disturbed lens histology and grave cataracts. Microarray transcript profiling showed an increase of mRNAs normally enriched in epithelial cells, consistent with an epithelialization of the transgenic fibers. Some aspects of fiber differentiation were unaffected, such as the expression of alpha- and beta-crystallins and aquaporins, whereas cytoskeletal remodeling, cell adhesion, organelle degradation, and antimitotic signaling were compromised. CONCLUSIONS Proper inactivation of FoxE3 expression at the lens equator is important for many aspects of fiber differentiation, and persistent expression leads to a partial epithelialization of fiber cells, with severe consequences for lens function.