Hedgehog Signalling

In this section you can look at the early development of zebrafish embryos and learn about Hedgehog signalling, a pathway very important during embryonic development.

Hedgehog proteins are messenger molecules that are absolutely essential for embryonic development. They are needed to do lots of important things during embryogenesis and they are also essential to keep adult organisms healthy. However, there are serious repercussions for embryos and adult organisms if hedgehog proteins get out of control.

For historical reasons proteins that are used by cells can end up with peculiar names. In this case, the function of this protein was first described in fruit fly (Drosophila). It was named Hedgehog because a larva that lacked the protein (i.e. a mutant larva) looked very spiky and reminded the discoverer of a hedgehog. The normal practice in science is that when you are the first to find a newtype of gene, you can name it!

Drawing of a confused hedgehog.

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.

Fish and Hedgehogs

In fish there are 5 hedgehog genes. As in mammals, Sonic hedgehog appears to be the most important member of this gene family.

An illustration demonstrating Hedgehog patterning.

Sonic hedgehog is produced in the notochord, a structure that runs through the middle of the embryonic trunk. The hedgehog signal from the notochord influences the behaviour and function of all the tissues surrounding it:

Just above the notochord lies the spinal cord (called the neural tube in an embryo). Cells in the neural tube close to the notochord receive lots of Hedgehog messages and this instructs them to become the <strong>motor nerves</strong> that make the tail muscle move.

Below the notochord lies tissue that is instructed by Hedgehog signalling to form the main artery of the trunk, the aorta.

To the left and right of the notochord lies the tail muscle. It forms V-shaped segments, which allow the fish to swim.

Here the Hedgehog signal creates a special type of muscle cell: the slow muscle, which in adult fish appears as a darker, very thin layer of tissue that lies on top of the pale, so-called fast muscle.

The slow muscles are “marathon muscles”, important for long-lasting but slow movements. The fast muscles are “sprint muscles” that are used for rapid but short-lived movements.

Hedgehog Zebrafish muscle - normal and mutant.
Hedgehog Zebrafish muscle - normal and mutant.

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.