Lens-specific transcription factors and their roles in diagnosis and treatment of human congenital cataract

Specific DNA-binding transcription factors (TFs) are critical components of gene regulatory networks (GRNs) that govern lens growth and differentiation. Lens placode formation is controlled by Pax6, Six3, and Sox2. Lens vesicle formation and its separation from the surface ectoderm are regulated by AP-2α, Foxe3, and retinoic acid/retinoid-activated nuclear receptors. The lens precursor cells exit cell cycle via a coordinated action of Gata3, Pitx3, and Prox1. Lens fiber cell differentiation is controlled by ATF4/CREB2, c-Maf, Gata3, Hsf4, Pax6, Pitx3, Prox1, and Sox1. Lens morphogenesis requires intricate temporal and spatial control of gene expression that is executed through multiple links between TFs and extracellular signaling, including BMP, FGF, Notch, and Wnt pathways. Disrupted function of lens-preferred TFs results in multiple lens developmental abnormalities that range from the lack of lens formation, lost of primordial lens (aphakia), incomplete separation of the lens vesicle from the surface ectoderm (corneal-lenticular stalk), disrupted lens fiber cell differentiation, and retention of subcellular organelles including the nuclei. These developmental abnormalities are not compatible with lens transparency and result in congenital cataracts. These cataracts affect 1:2,500 individuals and are difficult to manage due to the age of the child and eye growth considerations, possible associated microcornea or microphthalmia, and risks of glaucoma and amblyopia. For example, up to ~40 % of children with bilateral cataracts develop glaucoma following surgery, particularly when cataracts are removed early in life. This review describes normal and abnormal lens formation through the perspective of TFs preferentially expressed in the lens, their contributions to the human pediatric cataracts, and current strategies in human genetic and clinical studies to identify novel cataract-associated genes to better understand molecular basis of these defects and its treatments.