Failures of cellular crowd control

Imagine a hectic public-transit commute. You are a passenger stepping onto a bus already crowded with people. As you find a seat, you see that new passengers keep coming, further decreasing the available room. Your skin nerves sense this invasion of personal space, making you and the other passengers uncomfortable. With not an inch to spare, you and your fellow riders collectively decide not to allow even one more person in the crammed vehicle.

During development, cells — like the passengers — monitor and adjust their rates of accumulation to produce organs of predetermined size. When the cells sense the organ is full of enough cells, they don't allow more cells to hop on board. Unlike fellow passengers on the bus, cells have no eyes or nerves. How can they determine when enough is enough? Scientists have long wondered how the mechanism responsible for this process worked.

Graduate student Wen-Hui Lien and Dr. Olga Klezovitch, members of Dr. Valeri Vasioukhin's laboratory and colleagues in the Human Biology Division, have discovered an important clue to the problem. They found the mutation of a gene called αE-catenin in the central nervous system causes a massive increase in the number of cells due to abnormal activation of an important developmental pathway called hedgehog.

The researchers believe the αE-catenin gene connects the adherens junctions — formed when cells come in contact with one another — with the developmental hedgehog pathway, and this connection supplies feedback for controlling the size of a developing organ. They propose a "crowd-control" mechanism where cells use the adherens junctions to connect increases in local-cell density with regulation of the hedgehog pathway to ensure that enough, but not too many, cells are being produced. The findings, which have implications for tumor development, were published in the March 17 issue of Science and were subsequently highlighted in Cell and The Journal of Cell Biology.

Cell proliferation

The researchers, along with lab member Tania Fernandez and Dr. Jeff Delrow, director of the Center's Genomics Resource, used a mouse model to study brain development. The mice with mutant αE-catenin genes were born with bodies similar to their littermates, but with more than a two-fold increase in total brain cells, creating abnormally large heads at birth. The defective mice failed to thrive and died two to three weeks later.

"This two-fold increase in total brain cells at birth is quite dramatic," Vasioukhin said. "During development, there are rigid mechanisms responsible for counting cell numbers and for determining how big the final organ is going to be. These mechanisms are very difficult to change. We saw αE-catenin played a very important role in the regulation of cell accumulation in the developing brain."

The study, funded by the National Cancer Institute, is part of the Vasioukhin Lab's ongoing research in cell biology. The lab team specifically investigates how cells communicate with one another in multicellular organisms. Cells are always in contact with neighboring cells. They form cell-adhesion structures to make connections with other cells in order to determine who their "neighbors" are and how many of them are present. Confirming the cell neighborhood helps cells make important cell-fate decisions to proliferate, differentiate or die. αE-catenin is one of the proteins found in specific cell-adhesion structures called adherens junctions.

Hedgehog pathway

The researchers believe their work may be an important piece in solving the puzzle of cancerous tumors. They think solid tumors may escape the usual "crowd control" of cell proliferation by destabilizing the adherens junctions, a frequently reported event in human cancers. The hedgehog pathway, critical for normal development, is abnormally active in many types of human cancers.

"We found that when αE-catenin is missing, the hedgehog pathway becomes more active and drives hyper-proliferation," Vasioukhin said. "We think that cells have no feedback to sense increase in cell density, so they keep proliferating." Vasioukhin next plans to study how αE-catenin is connected to the regulation of the hedgehog-pathway stimulation. "We know the two are connected, but we don't yet know how," he said. "We want to figure out which proteins are responsible for regulation."