Interplay of proliferation and differentiation factors is revealed in the early human eye development

Eye development is a consequence of numerous epithelial-to-mesenchymal interactions between the prospective lens ectoderm, outpocketings of the forebrain forming optic vesicles, and surrounding mesenchyme. How different cell types forming eye structures differentiate from their precursors, and which factors coordinate complex human eye development remains largely unknown. Proper differentiation of photoreceptors is of special interest because of their involvement in the appearance of degenerative retinal diseases.

Here we analyze the spatiotemporal expression of neuronal markers nestin, protein gene product 9.5 (PGP9.5), and calcium binding protein (S100), proliferation marker (Ki-67), markers for cilia (alpha-tubulin), and cell stemness marker octamer-binding transcription factor 4 (Oct-4) in histological sections of 5-12 -week human eyes using immunohistochemical and immunofluorescence methods.

While during the investigated developmental period nestin shows strong expression in all mesenchymal derivatives, lens, optic stalk and inner neuroblastic layer, PGP9.5 and S100 expression characterizes only neural derivatives (optic nerve and neural retina). PGP9.5 is co-localized with nestin and S100 in the differentiating cells of the inner neuroblastic layer. Initially strong proliferation in all parts of the developing eye gradually ceases, especially in the outer neuroblastic layer. Proliferating Ki-67 positive cells co-localize with nestin in the retina, lens, and choroid. Strong Oct-4 and alpha-tubulin immunoreactivity in the retina and optic nerve gradually decreases, while they co-localize in outer neuroblastic and nerve fiber layers.

The described expression of investigated markers indicates their importance in eye growth and morphogenesis, while their spatially and temporally restricted pattern coincides with differentiation of initially immature cells into specific retinal cell lineages. Alterations in their spatiotemporal interplay might lead to disturbances of visual function.