Hedgehog Signalling

Hedgehog in fruit flies

Professor Philip Ingham, the former director of the MRC-CDBG (now called The Bateson Centre), was one of the first scientists to start characterising this signalling molecule in fruit flies. Hedgehog is a signalling molecule. It is made in cells that ‘signal’ to the surrounding cells. In effect it is a message or instruction from one cell to those around it

Hedgehog mutants formed part of a class of fruit fly mutants that all had a comparable defect. It became clear that these were all lacking components that are required either to make the Hedgehog signal or to receive it. Together these components formed the Hedgehog signalling pathway.

Hedgehog proteins are morphogens that are secreted by particular cells within the embryo, leading to the establishment of a concentration gradient of Hedgehog protein in the area surrounding the source of Hedgehog signal.

Cells near to a Hedgehog-secreting cell see a lot of Hedgehog, because it is present in this locality at a high concentration.

The cells near to the Hedgehog-secreting cells interpret the signal to mean one thing, whilst cells further away see less hedgehog and read the instruction differently.

Up the evolutionary tree

As it became clear that the fruit fly Hedgehog protein is used for communication between cells, many researchers got excited and started to wonder whether a similar signal was active in vertebrates – the group of animals that includes us humans. Indeed, similar proteins were found and they were active in very interesting regions of the embryo. These regions of the embryo were already known to be organisers that told neighbouring cells what to do. Soon it became clear that vertebrate Hedgehog was in fact the messenger produced by these organisers.

Unlike the fly, vertebrates have multiple versions (homologs) of the Hedgehog gene. In mice there are three Hedgehog genes, which are called Indian Hedgehog, Desert Hedgehog (after mammalian hedgehog species) and Sonic Hedgehog (like the video game character) – scientists have a sense of humour too! Sonic Hedgehog is the best characterised member of this gene family, and it also seems to be the most important of the vertebrate hedgehog genes.

A great number of things go wrong when the Sonic Hedgehog gene is mutated. In fact, an embryo that has lost all Sonic Hedgehog function will not survive.

Hedgehog and Human Disease

Hedgehog signals are so important that an embryo without the normal set of them will not be born.

Rare exceptions occur where hedgehog is partially lost. Mutations that inactivate the human Sonic Hedgehog gene lead to a condition called “holoprosencephaly”, in which babies are stillborn with one cyclopic eye and other severe birth defects. These severe abnormalities are the results of too little hedgehog signalling in the brain during development of the embryo; fortunately this condition is very rare.

More frequently, cells can also activate the Hedgehog signalling pathway inappropriately. In this situation, proteins that normally make sure that the Hedgehog signalling pathway is switched off when there is no Hedgehog signal around, become defective (mutated).

The most important gene in this respect is named patched (the name was also first coined for the fruitfly gene, but all vertebrates, including us, have very similar genes). Since every person has two copies of each patched gene, loss of both gene copies is highly unlikely. However, the body of a human adult has so many cells that mutations in both copies can occur once in a while.

If mutations in the patched genes occur in a skin cell (often such mutations are caused by too much exposure to sunlight) this can make these cells cancerous, leading to basal cell carcinoma, which is actually the most common skin cancer.

Some people are unlucky and inherit only one good copy of patched, so a single mutation of the second copy of this gene suffices to activate Hedgehog signalling. They suffer from a disease called Nevoid Basal Cell Carcinoma Syndrome, and develop multiple skin cancers.