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March 6, 2006 -- No. 126
Familiar protein instructs
cells how to organize: study
CHAPEL HILL Ė A group of proteins known to play a role in development and in some cancers can signal directly to organize cells and instruct them which way to divide, a study indicates.
Previous research showed that the proteins, called Wnts, must be present for some types of cells to polarize, or organize themselves correctly. And itís known that loss of cell polarity is one of the first steps in tumor development when mutations in Wnts result in cancer.
But researchers were uncertain as to whether Wnt proteins themselves were directly polarizing cells.
"We know a lot about the details of how Wnt proteins work and what they interact with, but some of the very basic questions have gone unanswered," said Dr. Bob Goldstein, one of the lead authors of the study and associate professor of biology in the University of North Carolina at Chapel Hill College of Arts and Sciences.The study is published in the March issue of the journal Developmental Cell. In the paper, Goldstein and a group of scientists from Japan used different methods to reach the same conclusion: that Wnts directly polarize cells. The researchers decided to publish their studies together after crossing paths at a scientific meeting.
The study raises the possibility that some cancers and other diseases occur when Wnt fails to polarize a cell properly. Mutations in Wnt proteins have been linked to certain types of cancer in humans, including colon cancer. And mutations in a human Wnt gene can cause Tetra-amelia, a rare genetic disorder resulting in loss of limbs.
"Itís not yet clear that a failure of polarity will necessarily lead to cancer, but itís possible that it does," said Goldstein, also a member of the UNC Lineberger Comprehensive Cancer Center.
Most cells arenít perfectly round but have a distinct top and bottom. Cells must maintain this polarity Ė this particular arrangement of parts Ė in order to perform functions such as cell-to-cell communication, which is required for many activities, including normal cell division.
Goldstein studied embryonic cells in C. elegans, a tiny worm often used as a model for studying human cell biology. Using a simple tool to physically move the cells, he showed that their division machinery would align properly only when both Wnt and another protein, MES, were present. But the division machinery always aligned on the same side of the cell where Goldstein had presented the Wnt protein.
"The MES signal needs to be there, but it doesnít matter where itís placed," Goldstein said. But the Wnt acts as a positional cue to instruct the cell where its dividing line should form, the study suggests.
Then, by observing as the cells developed over time, Goldstein showed that the wormís endoderm, or precursor to the intestinal tract, always developed on the side from which the Wnt protein had been presented. That result suggests that the Wnt protein is also responsible for determining which side of the cell forms the endoderm.
The Japanese scientists, including the other lead author of the study, Dr. Hitoshi Sawa of the RIKEN Center and the Graduate School of Science and Technology at Kobe University, also studied Wnt signaling in C. elegans, but in cells that would give rise to either neuronal cells or skin cells. By using genetic techniques, Sawaís team presented Wnt signals to responding cells from unusual locations. The responding cells always developed receptors for Wnt on the same side from which Wnt has been presented.
"So the work told us that not only can a Wnt signal polarize a cell, but it probably does it directly," Goldstein said.
The other authors of the paper are Hisako Takeshita of the RIKEN Center for Developmental Biology, and Kota Mizumoto of the RIKEN Center and the Graduate School of Science and Technology at Kobe University.
Work from the Goldstein lab was supported by the National Institutes of Health and a Pew Scholarship in the Biomedical Sciences. Work from the Sawa lab was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology and the Japan Society for the Promotion of Science.
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