The link of FOXO1 and FOXO4 transcription factors to development of the lens.

Background: The FOXOs regulate the transcription of many genes, including ones directly linked to pathways required for lens development. However, this transcription factor family has rarely been studied in the context of development, including the development of the lens. FOXO expression, regulation, and function during lens development remained unexplored.

Results: In studies of the embryonic lens, we showed that both FOXO1 and FOXO4, which share many downstream targets, are expressed in a differentiation-state-specific manner, most highly in lens epithelial and differentiating cortical fiber cells. Their expression patterns and subcellular distributions suggest both shared and distinct functions. Stabilization of FOXO cytoplasmic pools involved their binding to the chaperone protein 14-3-3. FOXO association with β-catenin linked this transcription complex to fiber cell-specific gene activation. Inhibition of PI3K/Akt signaling promoted FOXO1/FOXO4 nuclear localization in lens epithelial and fiber cells and expression of the CDKi p27 in the lens epithelium where it has been linked to lens cell withdrawal from the cell cycle and initiation of the lens differentiation program. We showed that FOXO1 transcriptional activation is required for the induction of p27 when Akt signaling is blocked, demonstrating the linearity of the PI3K/Akt/FOXO1/p27 pathway.

Conclusions: PI3K/Akt signaling regulates FOXO-dependent lens cell differentiation.