Unrestrained retina too much of a good thing

May 18 2005

When primitive nerve cells begin forming an eye in the mouse embryo, they are programmed to build a retina. But the ability to see depends upon connecting the retina to the brain via the optic nerve. Unless these embryonic cells are given the right cue at the right time, they mistakenly form a huge eye that consists entirely of retina and lacks the optic nerve.

The discovery that the retina is the 'default' setting for development in the embryonic eye comes from research by neurobiologist Greg Lemke and his colleagues at the Salk Institute for Biological Studies, published in the current issue of Genes & Development. The scientists carried out their work on the laboratory mouse as a model of human biology.

"Our results suggest that the retina is effectively the default pathway for eye development in mammals," said Lemke. The Salk team showed that two chemical cues, or signalling proteins, must be present in the right place at the right time to shut down this default pathway and allow the optic nerve to develop.

The painstaking work of the Salk team has important consequences since controlling the fate of stem cells implanted into the brain is crucial if these cells are to be safely and effectively used in human therapy.

"This study gives us a fascinating insight into how the parts of the brain are laid out because it is likely that the same model applies throughout the nervous system," said Lemke. "There are likely to be other brain areas whose development relies on blocking a tendency to turn into the same cell types as their neighbor."

Lemke and co-authors Stina H. Mui, Jin Woo Kim and Stefano Bertuzzi studied eye development in genetically engineered mouse embryos that lacked the two signalling proteins Vax1 and Vax2. The mice developed normally until approximately 10 days after conception, at which point they started to develop one large, folded sheet of retina, instead of a retina and an optic nerve.

"We were fascinated by our results because they were so dramatic," said Lemke. "The layers of the retina were perfectly formed but the retina reached all the way to the brain and there was no optic nerve. In effect, without the restraining influence of Vax1 and Vax2 the brain had created one gigantic eye."

The Salk team then spent the next two years uncovering the mechanisms involved. "It's fairly easy to describe the effect but it's much tougher to explain what's going on," said Mui.

Using complex gene expression techniques, the researchers painstakingly discovered that the fate of the eye is determined over the space of just a couple of days by a complex yet remarkably efficient system. The stem cells in the embryo destined to become the eye start out as identical. In response to external chemical messages, a gene called Pax6 is activated and becomes a powerful switch that tells these 'eye' cells to start developing into the retina. If nothing happens to stop this process, all the 'eye' cells will continue along this developmental path until one, huge retina is formed. However, this is normally prevented when the 'eye' cells closest to the centre of the brain start to produce Vax1 and Vax2, which act as chemical brakes on Pax6. As a result, these cells turn into the optic nerve instead.

"Normally Pax6 is turned off in the ventral optic stalk to allow the optic nerve to develop," said Kim. "It's an incredibly efficient way to control development because you don't need a completely new pathway for a new structure."

"Pax 6 is a powerful and ancient gene for eye determination," noted Lemke. "It plays this role from fruit flies to humans. As a consequence, its expression must be highly regulated during development." Although the retina is obviously required for sight, Lemke points out that "it's possible to have too much of a good thing."