EMBL researchers discover key molecular “switch” in eye development of medaka fish

Researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg have discovered a molecular “switch” that guides the development of the eye in a fish called medaka. The interaction of two proteins determines whether cells divide or specialize at a key moment as the eye forms. Researchers are keenly interested in such switches because the decision to replicate or differentiate is crucial to many processes, from the proper growth of embryos to the development of cancer. The story appears in this week’s edition of Nature (February 19, 2004).

“The discovery of this novel protein-protein connection is a major step forward in understanding a basic biological process such as the tight control and delicate balance between cell proliferation and cell differentiation,” notes PhD student Filippo Del Bene.

At any one time, the body’s cells choose between one of two paths: either divide to produce exact copies of themselves (called “proliferation”) or to take on very specialized shapes and functions such as liver, brain or retinal cells (called “differentiation”). Building a fish – or a human – involves perfect timing in switching back and forth between the two processes. If cells specialize too early, organs won’t grow. If tissue continues to divide after it has specialized, tumors may form.

Group Leader Jochen Wittbrodt and PhD student Filippo Del Bene were studying a protein called SIX3, produced by cells that will form the head in medaka embryos. SIX3 helps cells develop into the retina and part of the brain. “This protein is so powerful that if a cell produces it at the wrong stage of development, a retina will form – even if it’s in the wrong place in the body,” Wittbrodt says.

Del Bene discovered that SIX3 can clamp onto another protein called GEMININ, known to researchers for its role in cell division. “If GEMININ is around, cells don’t divide,” Del Bene says. “It prevents them from copying their DNA, necessary for cell division.”

When GEMININ is active at the wrong time, it disrupts cell division, making retinal cells specialize too early. Del Bene and Wittbrodt showed that when SIX3 locks onto it, GEMININ is unable to stop division, and the tissue grows to its proper size. When the cells have reached their normal size, GEMININ needs to unlock itself from SIX3 to become active again, so that tissues don’t become too large. Building the eye requires subtly shifting between amounts of these two proteins at the right times.

“This process of switching back and forth is necessary in the tissues of all organisms,” Wittbrodt says. “It’s fascinating to find that just two molecules play a fundamental role in the medaka eye. There may be similar switches in other tissues and other organisms. This gives us a good place to start looking.”