Cholesterol Linked to Cyclopic Animals

Certain naturally occurring toxins can cause animals to give birth to young with a single eye and a malformed brain. Part of the reason, researchers propose in tomorrow's Science, is that the toxins prevent embryonic cells from responding to a crucial molecular signal. The toxins do so, the team suggests, by interfering with the movement of cholesterol within cells. This finding, along with other work, is leading some researchers to speculate that cholesterol could hold a key to fighting similar birth defects in humans.

The defect-inducing compounds, or "teratogens," became notorious by the early 1960s when a rash of cyclopic lambs led investigators to a teratogen-rich plant called the corn lily, which the ewes had eaten. Now, researchers led by Philip Beachy of the Johns Hopkins University School of Medicine in Baltimore are studying how these teratogens affected a developmental signal called Sonic hedgehog (Shh), which guides the development of many parts of the body, including the forebrain and the face. Cells treated with the toxins ignored the Shh protein, failing to turn on and off the genes that Shh normally controls. "There's an active signal present, but no response," says Beachy.

A possible clue to why came from the distribution of cholesterol in treated cells. The researchers found excessive levels on the cell surface and a shortage in the endoplasmic reticulum (ER)--the cellular compartment where cholesterol is made. It makes sense that defective cholesterol movement might interfere with Shh signaling, says Beachy. A target-cell protein called patched, which binds Shh and plays a critical role in signaling, contains a stretch of amino acids that is likely designed to sense cholesterol levels. Beachy speculates that a shortage of cholesterol at the ER, sensed by patched, might lock the protein into a state that blocks the Shh signal from being relayed or fired. That could cause development to go awry and lead to cyclopia.

Beachy's scenario is controversial, but the work is leading to a new appreciation for cholesterol. "This work opens up a whole new role for cholesterol and raises a lot of interesting questions," says Yvonne Lange, a cell biologist at Rush-Presbyterian-St. Luke's Medical Center in Chicago. Among the most tantalizing: whether a mother's diet and cholesterol metabolism play some role in determining the severity of the human birth defect, which can range from a subtle flaw--one upper incisor instead of two--to cyclopia.

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