Effects of endothelial cells on retinal neurogenesis

A critical stage in the development of the neural retina is retinal neurogenesis, when retinal progenitor cells exit the cell cycle and differentiate into retinal neurons and glia. The control of retinal neurogenesis is complex and both intrinsic and extrinsic factors take part in regulating this process. Whether and how ocular blood vessels, and more specifically, vascular endothelial cells (ECs) of these vessels, influence retinal development is unknown. Addressing this question is difficult because of the critical requirement for oxygen supply from the circulation during eye development.

Zebrafish embryos can obtain enough oxygen by diffusion from the environment during the first few days of development, thus enabling the study of retinal neurogenesis in vivo in the absence of a functional cardiovascular system. Using several zebrafish genetic mutants we have analyzed retinal neurogenesis in conditions where: 1. ECs and circulation are absent; 2. ECs are present but no circulation takes place; 3. circulation takes place but no red blood cells (RBCs) are present. We found that whereas, as expected, the absence of RBCs did not affect retinal neurogenesis, retinae in which ECs were missing or retinae with ECs but no circulation showed reduced size and delayed neurogenesis. However, in the presence of ECs retinal neurogenesis progressed whereas in the absence of ECs retinal neurogenesis largely failed. The mechanisms underlying the contribution of ECs to retinal neurogenesis are under investigation. The results of these studies should contribute to the development of cell or tissue replacement technologies such as retinal organoids.