Ectopic expression of AP-2alpha transcription factor in the lens disrupts fiber cell differentiation

AP-2alpha is a developmentally important transcription factor which has been implicated in the regulation of cell growth, programmed cell death, and differentiation. To investigate the specific function of AP-2alpha in differentiation of the lens, AP-2alpha was expressed in the differentiating lens fiber cells under control of the alphaA-crystallin promoter. Normally, AP-2alpha is selectively expressed in lens epithelial cells and expression terminates at the lens equator, where epithelial cells terminally differentiate into fiber cells. Ectopic expression of the AP-2alpha gene in the fiber cell compartment resulted in bilateral cataracts and microphthalmia in mice by 2 weeks of age. Histological evaluation of embryonic and adult transgenic lenses revealed a significant reduction in lens size and anterior shifting of the transitional zone. Two aspects of fiber cell differentiation were also blocked, including the migration of newly formed fiber cells and an inhibition in fiber cell denucleation. Correlated with these defects were expanded expression of E-cadherin in the lens transitional zone and reduced expression of the fiber cell-specific protein MIP (major intrinsic protein). Together, these data demonstrate that AP-2alpha acts as a negative regulator of terminal fiber cell differentiation through the regulation of genes involved in cell adhesion and migration.