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Cholesterol gets 'thumbs up' for role in digit development

to have a cholesterol molecule attached to work properly.

"In fact, Sonic hedgehog is the only protein known to be modified by cholesterol,"Chiang said.

Because cholesterol is typically found in cell membranes and thought to 'tether' proteins to cells, scientists speculated that cholesterol might inhibit the movement of Sonic hedgehog through the developing tissue. This unique modification might explain why concentrations of the protein were high at the site of its production and then tapered off with increasing distance from the synthesis site.

But previous studies in mice suggested that cholesterol promoted the movement of Sonic hedgehog, a counterintuitive proposal given cholesterol's supposed tethering ability.

To try and clear up cholesterol's role in digit patterning and the Sonic hedgehog gradient, Chiang and colleagues created mice with an altered form of the Sonic hedgehog protein to which cholesterol cannot attach.

They found that mice lacking cholesterol-modified Sonic hedgehog developed with malformed and ectopic, or out of place, digits. The second, or "index,"digits were stunted and misshapen, appearing more similar to a thumb than a normal second digit.

The researchers also examined mice in which only half of their Sonic hedgehog proteins could attach to cholesterol. Those mice developed normal digits 2 through 5 (index through pinkie), but had duplication of these digits anteriorly.

The findings suggested that Sonic hedgehog without cholesterol traveled further than normal, triggering the anomalous digit duplications.

Chiang and colleagues confirmed this microscopically, showing that the protein spread out more evenly across the limb bud (a weaker gradient) in mice lacking cholesterol-modified Sonic hedgehog compared to normal animals.

"We found that, without cholesterol, Sonic hedgehog moves more readily, far from its site of synthesis, all the way to the anterior part
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Source:Vanderbilt University Medical Center


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