Researchers at UC San Francisco are proposing a revolutionary new theory about the way cells communicate at long distance.
Their findings, published in the May 28 issue of Cell, derived from a study about how cells communicate during development in the fruit fly Drosophila melanogaster, but, they say, the theory could be applicable to some types of cell communication in many life forms.
The researchers were investigating the way in which cells communicate with one another about how to develop from the unspecialized cells that follow conception, to the specialized cells that make up the organs and limbs of a fully developed organism.
They focused their study on cell communication in the developing wing of Drosophila, and, in so doing, detected long, cellular extensions reaching from the unspecialized, or "undifferentiated," cells of evolving tissue to the signaling centers of distant, special cells within the wing that orchestrate development.
What these extensions, which they named cytonemes, do once they reach these signaling centers has not been determined. But the supposition - which if correct would be revolutionary - is that they relay back to the cells from which they originate messages about how to evolve, or differentiate - in other words, how to behave.
Until now, developmental biologists have assumed that this critical communication was initiated not by the target cells in need of instruction, but by the cells that transmit the instructions. Moreover, they have thought that the communication involved the signaling messengers migrating through the extracellular matrix to their destination - not by being transmitted through a conduit.
"If our theory is accurate," said the senior author of the study, Thomas B. Kornberg, PhD, a professor biochemistry and biophysics at UCSF, "it will cause developmental biologists to fundamentally rethink how these signaling molecules move, and how cells communicate with one another."
The theory is particularly provocative because it suggests that all normal cells of the body communicate the way the brain's neurons, or nerve cells, do - via cytoplasmic extensions.
"Our observations show striking parallels between cytoneme-bearing cells and neurons," said Kornberg. "We suggest that, contrary to conventional thinking, all cells communicate via these extensions - that they send out very long thin fingers to make contact over very long distances."
The signaling molecules that function as pattern organizers in evolving tissues, known as "morphogens," act by directing gene activity in their target cells. In recent years, researchers have identified some of these signals, including hedgehog secreted proteins and transforming growth factor (TGF) beta proteins, known as Dpp.
Scientists have assumed that morphogens are secreted by signaling cells, and that they somehow find their way, perhaps randomly, to the far-flung target cells in need of instruction. (The most favorable theory has been that they move from neighboring cell to neighboring cell, like a bucket brigade to fight a fire, a little bit spilling out with each pass off until the bulk of the morphogen reaches its destination.)
Regardless of the particular mode of transport, however, the theory has been that morphogens arrive at their destination at a particular gradient, or concentration, and that, in the concentration of the morphogen, lies the message of what the target cells are to do.
"The theory has been that the target cells differentiate into specific structures by interpreting their position with respect to boundary regions of a given area, and that they determine this position by interpreting the distinct morphogen concentrations they receive," said the first author of the study, Felipe-Andres Ramirez-Weber, PhD, a postdoctoral fellow at UCSF.
"If they receive a lot of the morphogen, they respond one way. If they get a little, another. This process is believed to be a basic mechanism that cells use to understand where they are in the developing animal."
(The existence of morphogen gradients has been detected in several developmental processes in flies and vertebrates, such as mice, suggesting that the existence of these gradients is likely to be a general feature of multicellular animals.) A fundamental puzzle about the way morphogens are transmitted has been that, while they have been supposed to be secreted, they don't move efficiently through the extracellular matrix. The hedgehog protein, in fact, is tethered tightly to the cell that makes it, and the transforming growth factor beta proteins, including Dpp, stick to extracellular matrix proteins.
"Cells that make Hedgehog hold onto it tenaciously, and matrix proteins adhere to Dpp," said Kornberg. "These are not properties you would expect of molecules that have to move in the extracellular environment."
Scientists have argued that scissors-like proteins known as proteases come along to release the morphogens. But the UCSF researchers propose the opposite explanation.
"We suspect that extracellular matrix proteins bind up these proteins to make sure they don't go anywhere," said Kornberg.
The researchers came to their conclusion by examining the mode of transmission of Dpp protein and Hedgehog protein in a region of the Drosophila wing that is subdivided into two equal regions, the anterior (A) and posterior (P) compartments, which bisect the wing region.
They focused on the line of cells running down the center of the wing disc that is responsible for organizing and emitting Dpp, and they tried to determine how the signal moves to its destination in far-flung cells of the wing.
They did so using a new technology that involves using a green fluorescent protein as a tracer. "When we lit up cells far away from the Dpp-expressing swath of cells using this new technology, we could see they had these tiny little extension that appear to connect," said Kornberg.
These cytoplasmic extensions reached to the central portion of the disc, and were polarized towards it, suggesting that they traffic the Dpp signal. "These features suggest that the cytonemes in this region of the wing link outlying cells to the disc centers, allowing cells of the A/P signaling center to directly contact more distant cells," said Ramirez-Webber.
Now, to determine if cytonemes actually function as the conduits for the chemical signals, the researchers are developing systems in which two cells communicate with each other - one sending signals, one receiving - and restricting the mode of communication to cytonemes. If they can determine that the cells communicate via these processes, they will have established the cytoneme's function.
"If the finding bears out," said Kornberg, "it could cause people to rethink how they think these molecules move, and how cells communicate with one another. This would represent an entirely different way of looking at it." The UCSF study was funded by the National Institutes of Health and the Merck Genome Research Institute.
Journal
Cell