Human tissues and organs are comprised of a multitude of individual cells. In order to build and maintain complex structures like bone and the intestine, these individual cells must communicate with each other to coordinate their actions. Cells communicate by sending out instructions in the form of signalling molecules. These signals are recognised by neighbouring cells, leading to the activation of specific signalling pathways. By regulating cell growth, death and differentiation these signalling pathways ensure organs and tissues develop to the right size, with the necessary specialized cell types needed to function correctly. Furthermore, in adult tissues and organs signalling molecules ensure tissues regenerate to replace lost or damaged cells.
As we age these signalling pathways change, with drastic consequences for human health. In addition to the loss of tissue renewal seen in age-related diseases such as osteoporosis, altered signalling environments can also favour the uncontrolled cell growth that causes cancer. Establishing how cells signal to each other, and how these signalling systems become dysfunctional with age, will uncover how age-related diseases develop and potentially identify therapeutic interventions for their treatment.
We study two particular signalling molecules, Wnt and Hedgehog, both of which carry hydrophobic lipid modifications that complicate their ability to spread between cells and function in cell-to-cell communication. We seek to understand how these lipid modified signals are released from sending cells, how they are recognized on receiving cells and how recognition leads to activation of signalling. In addition to identifying precisely how the Wnt and Hedgehog signalling pathways operate at the cellular level, we seek to identify how they, and other signalling pathways, change in ageing organs and how such changes affect organ function. To answer these questions, we use a multidisciplinary approach involving protein and molecular biology, human cells, organoids, and Drosophila melanogaster (fruit fly) and mouse genetics.
An example of cell-to-cell communication in the developing fruit fly wing. Here a strip of cells in the middle of the organ signals to neighbouring cells by releasing a specific Wnt signalling protein called Wingless (green). Wingless spreads to and instructs neighbouring cells that receive a large amount of Wingless to switch on a specific gene called senseless (red). While those cells that receive high and medium levels of Wingless switch on a different gene called Distal-less (purple). This communication helps the developing organ to grow and attain the right cell types.