West, Heloise; (2003) Control of retinal astrocyte numbers during development of the retina. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Retinal astrocytes are associated not only with retinal neurons but also with the retinal vasculature during development. They control vascular development after birth, attracting vascular cells to invade the retina from the optic nerve head and spread out towards the periphery. It is not clear what controls growth of the astrocyte population itself. To address this I looked at control of retinal astrocyte proliferation during development. I showed that astrocytes migrating ahead of the spreading vasculature are highly proliferative but, once caught up by the vessels, they stop proliferating. The proliferative, avascular regions are also associated with up-regulation of VEGF expression. Since VEGF is known to be upregulated under hypoxic conditions in vitro, these observations suggest that oxygen concentration might be instrumental for controlling astrocyte gene expression and proliferation in vivo. To test this idea I manipulated oxygen levels in vivo by keeping mice in hyperoxic conditions (80% oxygen), which limits development of the retinal vasculature and gives rise to regions of both hypoxia and hyperoxia. I found a positive correlation between astrocyte proliferation and areas of hypoxia, implicating oxygen as a negative regulator of retinal astrocyte proliferation in vivo. I also showed that astrocytes proliferate at a higher rate in low oxygen in culture. Taken together, my findings suggest that oxygen, brought into the retina by the developing vasculature, is responsible for shutting down proliferation of astrocytes, thus preventing further vascular development in a homeostatic feedback loop. I also show a developmental phenotype in the eyes of mice lacking the Ink4a/Arf locus. The Ink4/Arf locus encodes two proteins - pl6Ink4a and pl9Arf. These proteins have been shown to trigger G1 growth arrest in vitro and to act as tumour suppressor proteins in vivo. In the absence of these two proteins, excess cells accumulate in the hyaloid vasculature. A simple explanation based on these and other observations is that Arf prevents over proliferation of cells in the hyaloid vasculature during development.

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