Gene Trigger For Pancreas Formation Identified

"It has been established that islet cell transplantation can solve the diabetes problem," said Wright, referring to studies carried out in Edmonton, Canada and elsewhere. "The problem is having a suitable and sufficient source of transplantation material."

Donated pancreases and the technical expertise required to isolate functioning islet cells--the pancreatic cells that produce insulin--will not meet the demand, Wright said. An alternative, he said, is to produce insulin-secreting cells from embryonic or other stem cells.

"If we can identify the factors that determine pancreatic cell fate," he said, "we might be able to coerce embryonic stem cells or other cells to turn into pancreas."

One of these factors is a gene called PTF1p48 (p48 for short). Wright and colleagues reported in Nature Genetics, published online August 19, that p48 is required for the development of the pancreas, both its exocrine cells--those that secrete digestive enzymes--and its endocrine cells--those that secrete insulin and other hormones.

Wright's team used what one reviewer of the paper called "a novel and powerful cell marking method" to track cells in the mouse that express the p48 gene, starting very early in embryonic pancreas formation. The method relied on genetic manipulations to introduce an inherited marker--a blue color that could be followed in cells that turned on the p48 gene, and in all the cells that came from those cells.

A simple way to think about the technique, Wright said, is to picture the crowd at a football stadium and to imagine that somewhere in the stadium, for a limited time, a man gave away unique blue hats and asked people to wear them. "Now we can follow the people who got hats, no matter where they go," Wright said. "Whether they go to get a hot dog or leave the stadium entirely, we can find them."

Using the technique, the investigators found and followed the cells that turned on the p48 gene--as if these cells were wearing blue hats. The cells that bud out to form the pancreas turned on p48; they were blue. And the cells of the mature pancreas were blue too.

Wright's team combined this powerful method for tracing a cell's lineage with gene knockout technology. They engineered mice to lack the p48 gene, causing abnormal development of the pancreas. Cells in these knockout mice still try to turn on the p48 gene, so the investigators were able to follow the blue marker in these cells.

They found that, with p48 absent, the cells that normally express p48 an