Controlling body size by regulating the number of cells

Why are elephants bigger than mice? The main reason is that mice have fewer cells. Research published in Journal of Biology this week uncovers a key pathway that controls the number of cells in an animal, thereby controlling its size.

Ernst Hafen and his colleagues from the University of Zürich used fruit flies to investigate the role of the insulin-signalling pathway and in particular a molecule called FOXO. If insulin signalling is reduced, for example by starving developing fly larvae, FOXO activity increases; this then reduces the number of cells in the developing flies, causing them to be smaller.

Mammals have similar a signalling pathway, and it has been suggested to have a role in tumour formation. Hafen’s work gives us more insights into how disruption of FOXO function can lead to cancer.

The researchers used a combination of genetic techniques, over expressing FOXO in parts of the fly and analysing flies that contained no functional FOXO protein, to investigate what FOXO does. They found that flies with no functional FOXO looked normal but were more sensitive to oxidative stress, thought to be a cause of ageing. Increasing the amounts of highly active FOXO protein in the developing fly eye caused many of the eye cells to die. However, the real clue to FOXO’s function came from studying the effect of removing functional FOXO protein from flies that have a reduced ability to signal downstream of insulin.

Normally, reducing insulin signalling in developing flies causes these flies to become smaller as they have fewer, smaller cells. Yet without FOXO, these flies do not suffer such a severe size reduction. This is because they have more cells than normal insulin signalling pathway mutants. These experiments suggest that FOXO plays a role in reducing the number of cells in the developing fly if insulin is not present, by inhibiting cell division.

Hafen and his co-authors write, “In this study we provide genetic evidence that the Drosophila FOXO homolog, dFOXO is an important downstream effector of Drosophila insulin signalling and regulator of stress resistance”.

The insulin-signalling pathway may provide a crucial link between nutrient availability, stress and growth, thus allowing animals to respond appropriately to their environment.