Communication between cells is primarily based upon the interaction of signalling molecules and the appropriate receptors. At close distances, cells normally exchange information through direct contact using surface bound signals or communicating junctions. However, longer distances are frequently covered by soluble signalling molecules that are released into the bloodstream, or interstitial fluid, in order to bind to distant target cell's receptors. Nerve cells have so far been the only cells known to be able to communicate over large distances by direct contact. As they develop and grow,nerve axons continuously sense guiding signals through receptors found on the axon tips, which are enlarged by cellular protrusions called filopodia. In a careful study published in Nature, Cyrille de Joussineau and colleagues provide the first clear evidence that epithelial cells from Drosophila imaginal discs use similar filopodia to send signals to non-adjacent cells in the neighbourhood.
Drosophila imaginal discs are sacks of epithelial cells, which sprout and differentiate during the insect's development. When the larvae pupate, the imaginal discs provide precursor cells to make various adult fly structures, such as wings, legs and sensory bristles. Developmental biologists have shown that the adult fly's mechanosensory bristles are derived from single epithelial cells found in proneural clusters of initially equivalent imaginal disc cells. During differentiation one epithelial cell is singled out per cluster to become a neural cell, known as the sensory organ precursor. What is of interest is that once formed, the sensory organ precursor cell prevents other epithelial cells within the cluster from taking the same developmental path. However, neural differentiation is not only inhibited in adjacent cells, but also in cells that are located further away in the cluster. There is some evidence in the literature that this process, known as lateral inhibition, involves a conserved signalling pathway frequently found in cell fate determination, called Delta/Notch-signalling. This pathway normally involves two membrane bound components called Delta and Notch, which are presented on the surfaces of different cells. The Delta protein is a ligand for the Notch receptor, transmitting a signal from one cell to another. For this reason Delta/Notch signalling requires direct contact between cells. Yet it was not easy to explain how the sensory organ precursor is communicating the Delta/Notch signal across the proneural cluster consisting of thirty cells or more when not all of the cells appear to be in direct contact. It has been known that other imaginal disc cells sense gradients of signalling molecules in order to coordinate patterning. And they also receive morphogenic signals from both close and distant cells through filopodia-like processes. Could filapodia mediated Delta Notch-signalling be involved in lateral inhibition?
To test their hypothesis, de Joussineau and colleagues constructed transgenic flies expressing tagged versions of the Delta-protein to see its expression pattern. They found that the filopodia of sensory organ precursor cells indeed contained Delta-protein, suggesting that filopodia bridge distances to deliver Delta and activate Notch-receptors, even to remote cells in the cluster.
Next they tested whether the filopodia mediated long-range Delta-signalling by disrupting the actin-based cytoskeleton and preventing filopodia formation,to see whether that resulted in a reduction in the range of lateral inhibition and caused the flies to develop an excessive number of mechanosensory bristles. Indeed, when the French team did this, they observed a significant increase in the number of mechanosensory bristles of the adult fly, indicating that, as a result of missing filopodia that block neural differentiation, some of the cells within the clusters have additionally differentiated into sensory organ precursor cells.
So far, epithelial cells have been thought to communicate exclusively by direct contact between neighbouring cells or by signalling molecules present in the extracellular space. However, the finding that epithelial cells are able to contact and communicate with distant cells using filopodia demonstrates that epithelial communication is more colourful than previously thought. This new mode of communication may also serve physiological functions other than growth and development and may allow the exchange of information between different cell and tissue types.
