Temporospatial induction of homeodomain gene cut dictates natural lineage reprogramming

As an embryo develops, an organism transforms from a single cell into an organized collection of different cells, tissues and organs. Regulated by genes and messenger molecules, non-specialized cells known as precursor cells, move, divide and adapt to produce the different cells in the adult body. However, sometimes already-specialized adult cells can acquire a new role in a process known as lineage reprogramming. Finding ways to artificially induce and control lineage reprogramming could be useful in regenerative medicine. This would allow cells to be reprogrammed to replace those that are lost or damaged. So far, scientists have been unable to develop a clear view of how lineage reprogramming happens naturally. Here, Xu et al. identified a cell-conversion event in the developing fruit fly. As the fly larva develops into an adult, a group of cells in the midgut reprogramme to become renal cells – the equivalent to human kidney cells. The experiments revealed that a combination of signals from a cell messenger system important for cell specialization (called Wnt) and the hormone that controls molting in insects, activate a gene called cut, which controls the midgut-to-renal lineage reprogramming. Together, Wnt and the hormone ensure that cut is activated only in a small, specific group of midgut precursor cells at a precise time. The reprogrammed cells then move into the excretory organs, the renal tubes, where they give rise to renal cells. Midgut precursor cells in which cut had been experimentally removed, still traveled into the renal tubes. However, they failed to switch their identity and gave rise to midgut cells instead. Further examination revealed that both Wnt and the ecdysone hormone are needed to activate the cut gene. This is probably achieved by creating loops in the DNA to bring together the two distantly located key regulatory elements of cut gene expression. If this mechanism can be seen in other contexts it may be possible to adapt it for medical purposes. The ability to reprogramme groups of cells with high specificity could transform medicine. It would make it easier for our bodies to regenerate and repair.