Bring out your dead cells

Sometimes telling your neighbor “Eat me,” is a good thing. That is if you happen to be a dead or dying cell whose carcass needs disposal.

Scientists at RockefellerUniversity in New York City have discovered a protein that turns some fruit fly brain cells into semiprofessional undertakers. The discovery may shed light on what happens to millions of neurons as the brain remodels itself throughout life.

Researchers led by Ulrike Gaul, a Drosophila geneticist at Rockefeller, dubbed the newly discovered protein Six-Microns-Under, or SIMU, in honor of an HBO series called Six Feet Under about a family that runs a funeral home.

“We had to take some poetic license because cells in the fly are often less than six microns in diameter, but it was too good a name to pass up,” Gaul says.

SIMU anchors itself in the membrane of a type of brain cell called a glial cell. Glia get their name from the Greek word for glue, and, for a long time, scientists thought the cells did little more than hold the brain together and provide nourishment and support to neurons. But in recent years, glia have gained new respect with discoveries that the cells help regulate connections between neurons and perform other vital functions in the brain. In vertebrates, including humans, as many as 90 percent of cells in the brain are glia.

Gaul’s study, published May 2 in Cell, shows that glia perform another crucial housekeeping duty: bringing out the dead. In the rest of the fly body, white blood cells perform this task. But the fly brain puts up a barrier these white blood cells can’t cross. It has been a mystery until now exactly which cells in the fruit fly brain act as funeral directors and how they accomplish the task.

The new study shows that a particular type of glial cell eats the corpses of its neighbors and that SIMU helps the glial cells recognize the dead. The glial cell literally engulfs the dead cell, and special compartments within the glial cell digest the dead cell.

The job’s importance is often underestimated, says Kodi Ravichandran, an immunologist and molecular biologist at the University of Virginia in Charlottesville who was not involved in the study. He wrote a preview article of the study that appears in the same issue of Cell.

During development, organisms make many more cells than they actually need and must cull excess cells. The roundworm Caenorhabditis elegans intentionally kills about 10 percent of its cells as it matures. In the fruit fly Drosophila melanogaster, as many as 40 percent to 50 percent of cells in certain tissues hit their internal self-destruct buttons. Something has to clear away the corpses, which can spill destructive enzymes on healthy cells or trigger suicide in their neighbors.

Usually, undertaker cells called phagocytes gobble up dead cells so quickly the process isn’t even noticed, Ravichandran says.

“It’s like a garbage man that you don’t appreciate until he or she stops picking up,” he says.

When cells die they hang out the molecular equivalent of toe tags so their neighbors will know they’ve given up the ghost. But the tags can take many forms and not all phagocytes, which include white blood cells, are able to decipher the “eat me” message on each dead cell. Six-Microns-Under and other receptors probably read different tags and work with other proteins to set off a feeding frenzy to clear the corpses.

Mammals don’t have SIMU, but they do have proteins that contain the portion of SIMU that likely reads the toe tags. Understanding how this recognition process works in fruit flies could also help in understanding similar functions in mammalian cells.

Gaul and her colleagues don’t yet know which “eat me” signal or signals attracts Six-Microns-Under or what other proteins it partners with to get rid of the dead cell bodies.