Abstract:

Many blinding diseases, such as retinitis pigmentosa, age-related macular degeneration, and glaucoma involve the permanent loss of retinal neurons, especially photoreceptors or the centrally projecting retinal ganglion cells. Stem cells have been proposed as a potential source of cells for neuronal transplantation, due to their capacity for proliferative expansion and the potential to generate different retinal cell types. Understanding the developmental biology of retinal cells will be the key to the success of such a strategy. In the developing retina, a complex series of transcription factors sequentially activates genes involved in development, thus defining the adult cell type. Among these, the LIM-homeodomain transcription factor Islet-1 (Isl1) is expressed by developing and mature ganglion, cholinergic amacrine, ON-bipolar, and horizontal cells in the retina of most of the vertebrates that have been studied. Because Isl1-null mutant mice die at embryonic day 9.5, before the onset of retinogenesis, the role of Isl1 in retinal neurogenesis remained largely unknown. However, Isl1 conditional knockout has been generated to identify the exact role of Isl1 in retinal development. Thus, the conditional inactivation of this transcription factor during mouse retinogenesis disrupts retinal function and also results in marked reductions in mature bipolar, amacrine, and ganglion cells, and a substantial increase in horizontal cells. Therefore, Isl1 seems to play a highly conserved role in cell specification, differentiation, and maintenance of phenotypes of retinal cell types. An understanding of factors such as Isl1 that are involved in vertebrate retinogenesis might be exploitable to reprogram transplanted retinal stem cells.