Sonic Hedgehog, essential for normal limb development

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Sonic Hedgehog, essential for normal limb development

20-Aug-2004 News-Medical.Net

http://www.news-medical.net/?id=4219

Fingers are key to the art of communication, whether it’s a politician

flashing a thumbs-up to a cheering crowd or a bride displaying a

diamond-bedecked ring finger.

Now scientists at the University of Florida and Harvard University have

described how the art of cellular communication how cells “talk” and

what happens when they stop plays a crucial role in normal limb

development and the formation of digits in mice, a discovery that sheds

light on the same process in people. The researchers detail their

discovery in today’s issue of the journal Cell.

Why the five fingers on a hand form into the sizes and shapes they do,

and the fundamental mechanisms that cause some people to be born without

fully formed fingers or extra fingers has been a mystery until now.

Understanding the development process could someday help doctors correct

defects before birth, or help regenerate limbs lost to accident or

amputation, researchers say.

“Everybody’s goal is to figure out the normal process well enough so

then you can go back and maybe help a human,” said Harfe, a

developmental biologist at UF’s College of Medicine and the paper’s lead

author. “For example, if a baby is missing a pinkie, and we have learned

enough about how this digit is formed in the first place, we might

eventually be able to repair the defect by using what we know to induce

a normal digit to grow.”

The findings also could shed light on the development of the body’s

more-critical organs, he said.

“This is the first time anyone has figured out how the body regulates

the size — not just of the limb, but possibly of other organs during

development,” he said.

The researchers studied cells in the mouse embryo limb bud that express

an active gene called Sonic Hedgehog, which is essential for normal limb

development. The gene expresses a protein that acts like a dispatcher,

barking chemical orders to other molecules and initiating limb growth.

The researchers followed the cells that expressed the gene and found

that in many of these cells, the Sonic Hedgehog gene eventually stops

sending its message and migrates to another part of the developing limb.

These cells then form a “wedge” that directly blocks another important

signaling pathway in the limb. When communications break down between

key molecules, the signal for limb growth shuts down at the right time

and a normal limb results.

Although the discovery was made in mice, scientists say the same pathway

is believed to function in human cells.

Harfe, an assistant professor of molecular genetics and microbiology,

studied mice bred to harbor a pair of visible genetic markers in Sonic

Hedgehog-expressing cells. That enabled him to follow what happened to

the cells as a limb developed, even after they stopped expressing the

gene.

“Sonic Hedgehog turns off as you start to form the fingers,” Harfe said.

“Previously we had no way of following what happens to the cells that

were expressing this gene once it turned off. We needed to design a way

to follow the fates of these cells once they stopped expressing the

Sonic Hedgehog gene. Once we did that, we learned that they formed this

wedge and that the cells that formerly expressed Sonic Hedgehog actually

form the last two fingers.”

Harfe found that the length of time and the concentration of Sonic

Hedgehog that cells were exposed to determined which digit the cells

would form.

“There has always been a huge debate in the field as to how you get a

pinkie as opposed to an index finger or a thumb,” Harfe said. It is

known that Sonic Hedgehog is expressed in a gradient, or in a decreasing

concentration over distance, he said. “What we found is that both of the

last two digits are formed directly from the cells that formerly

expressed Sonic Hedgehog.”

The cells that were exposed to the highest concentrations of Sonic

Hedgehog, both because they were closest to it and for the longest

periods of time, become the fourth and fifth digits in mice, akin to the

ring and pinkie fingers in people. The digits farther away from the

source of the gene form the second and third fingers, analogous to the

index and middle fingers in people. The cells with no exposure to Sonic

Hedgehog form the thumb, or first digit.

Sun Xin, an assistant professor of medical genetics at the University of

Wisconsin at Madison, said, “I think Dr. Harfe’s research described in

the Cell paper is very important to the limb development field. The

research allowed the authors to put forward a new model of how different

structures form along the anterior/posterior axis of the limb. It will

allow us to rethink the role of many other molecules involved in

anterior/posterior patterning.”

http://www.ufl.edu