New Gene Reduces Retinal Degeneration In Fruit Flies

In teasing apart the molecular interactions and physiology underlying light perception, the researchers studied a gene they dubbed “Lazaro” that is expressed 15 times higher in the fly eye than the rest of the fly head. They found that this gene is required for a second biochemical pathway that controls the activity of a protein called the TRP channel. TRP channels are found in fruit fly neurons responsible for sensing light. The fly TRP channel is the founding member of a family of related proteins in mammals that are essential for guiding certain nerves during development and for responding to stimuli including heat, taste and sound.

By shining bright light onto and recording electrical changes in single nerve cells in the fly eye, researchers found that neurons carrying a mutation in this gene cannot respond as well to light as compared to neurons carrying normal copies of this gene. In fact, the mutant neurons turn off their response to light four times faster than normal neurons. Because Lazaro helps fly TRP channels work at their maximum, it is possible that a Lazaro-like gene in mammals might also play a role in how well mammalian TRP channels work.

“These results have implications for understanding sensory signaling in mammals,” says the study’s senior author, Craig Montell, Ph.D., a professor in the biological chemistry department in the Institute of Basic Biomedical Sciences at Hopkins.

The researchers also discovered that alterations in this new gene greatly reduce the retinal degeneration caused by a different mutant. They named this new gene Lazaro after the novel Lazarillo de Tormes, in which the orphan boy Làzaro helps a blind man see.

Of the molecules known to control TRP channels, a key player is diacylglycerol, known as DAG. DAG is known to be made by a well-studied biochemical pathway. The researchers found that Lazaro provides a second way to make DAG, enabling the cell to make more DAG.

Why is there a second pathway for DAG production? “We think Lazaro is priming the system for maximal light response,” says Montell.

DAG can be metabolized to polyunsaturated fatty acids, which have been shown to control TRP channels in flies and may also control some mammalian TRP channels. However, exactly how these molecules exert their control remains unclear. In adding the Lazaro gene to the list of players, the researchers hope to learn more about how TRP channels are controlled.

The researchers were funded by the National Eye Institute.

Authors on the paper are Young Kwon and Montell, both of Hopkins.