Cholesterol has had nothing but bad press since scientists discovered that it was responsible for clogging arteries and causing all manner of health complications. But according to researchers at the Vanderbilt University Medical Center, cholesterol is also responsible for us developing the correct number of fingers and toes in the correct locations. This gives a new bent to an old nursery game, where the "little piggy" that "had roast beef" also didn't have a superfluous toe. The new study, published in the Proceedings of the National Academy of Sciences, states that if cholesterol doesn't attach itself to an important developmental protein responsible for controlling digit patterning, mice grow extra digits that often appear in abnormal places. Senior study author Dr. Chin Chiang studied the crucial digit mapping protein, affectionately dubbed Sonic Hedgehog, in the early 90s. He showed that without Sonic Hedgehog, mice would develop either a thumb on the front paw or a big toe on the hind paw. Today, Dr. Chiang's work has culminated in findings that elucidate on some long-standing scientific controversies in regard to limb development.
High concentrations of Sonic Hedgehog are produced by specialist cells positioned at a posterior location of the developing limb bud, which then form either the little finger or toe. As the limb bud develops, the protein disperses into weaker concentrations (represented as a gradient) that express the remaining digits. When this process goes awry and Sonic travels to tissue where it doesn't belong, extra digits form. This condition is known as polydactyly. "Questions have remained about what regulates the Sonic hedgehog gradient," said Chiang. "And we've been working on that for a number of years."
The answer remained a mystery until researchers realized that Sonic Hedgehog needed the attachment of a cholesterol molecule for proper function. "In fact, Sonic hedgehog is the only protein known to be modified by cholesterol," said Chiang. But this realization only came after the transcendence of some assumptions surrounding the properties of cholesterol.
The controversy surrounding limb development has mostly been in regard to the properties of cholesterol. Traditionally cholesterol has always been thought to bind proteins to cells, so scientists speculated that cholesterol might inhibit the movement of Sonic Hedgehog through developmental tissue. This, they thought, would explain why concentrations tapered off the further the protein moved from its source. But other studies paradoxically showed that cholesterol actually encourages the movement of Sonic Hedgehog. To solve the mystery, Chiang set about creating an experiment that involved mice with a modified form of the Sonic Hedgehog protein that could not bind to cholesterol, or one that would only bind to half the cholesterol molecules.
Chiang's findings showed that mice with the modified version of Sonic developed misshapen, oddly located (ectopic) digits, where the second index digits appeared more like a thumb. Mice with Sonic that could attach to only some cholesterol molecules developed normal digits, but they were also duplicated anteriorly. The conclusion: the Sonic Hedgehog protein without cholesterol moved further than normal, which resulted in irregular digit replication. "We found that, without cholesterol, Sonic Hedgehog moves more readily, far from its site of synthesis, all the way to the anterior part of the limb bud where it is normally never detected," Chiang explained.
Researchers are still unsure as to why polydactyly occurs in humans, but they suspect that it might have something to do with mutations in the Sonic Hedgehog signaling pathway. Errors in Sonic also give rise to other conditions aside from limb deformities, such as cancer and a congenital condition of the forebrain called holoprosencephaly. At present, Chiang and his team are researching the cholesterol-modified Sonic Hedgehog protein in the developing brain and spinal chord, which may result in the prevention of certain birth defects. "We are finding some surprises," Chiang said, "suggesting that the function of cholesterol is different in these different tissues."
Source: Vanderbilt University
