It’s Not Good to Think Outside the Homeobox

It was a very good question in my class last week – a series of them actually – that stimulated me to prepare this post.

We were talking about the development of limbs and how the formation of the various bones is directed by the action of homeobox or HOX genes. HOX genes are highly conserved among animals, meaning that the same gene in humans is likely to also be found in fish or even more distantly related animals, like fruit flies.

HOX genes direct the development of the overall body plan of animals. They help the developing organism differentiate between the head-end and the tail-end of the animal. HOX genes regulate the formation of bones in limbs, insuring the common pattern shared among all land vertebrates and the lobe-finned fishes.

But… Why are they called ‘homeobox’ or HOX? And how do they actually work?

A homeobox is a strand of DNA that is about 180 base pairs long. This homeobox encodes a 60-amino acid protein called a homeodomain, which is important in the overall development of an organism’s body plan. The homeodomain has a specific structure having three alpha helices connected by short loops.

HOX genes are genes that contain the homeobox unit. Typically several of these genes occur sequentially on a single chromosome, forming a cluster. In vertebrates, there are four clusters called HOXA, HOXB, HOXC, and HOXD. Other organisms have fewer clusters of HOX genes, but the homeobox is virtually the same for all HOX genes in all animals. HOX clusters are always related to development of the animal’s body plan from head to tail, and in other directions (like back to front, or dorsal to ventral) in organisms that have more complex body plans.

There are other genes that also help direct the formation of the body during early development that are not HOX genes, but they work the same way. The important distinction is that HOX genes have the homeobox, and other developmental genes do not.

One of these not-HOX but important developmental genes is called Sonic hedgehog. This gene helps regulate the formation of the limb, alongside members of the HOXA and HOXD clusters. The Sonic hedgehog gene is active only at the posterior (tail-end) part of the developing limb, close to the body (like in the proto-armpit, if that helps). It creates a protein that decreases in concentration away from this point. The amount of the Sonic hedgehog protein detected by the embryonic tissues determines what part of the limb will form (like upper arm, or hand) and also which side (pinky finger side or thumb side).

Sonic hedgehog is found in all vertebrates that have limbs. It is also seen in sharks directing the formation of fins (including the scary dorsal fin).

So to summarize:

HOX genes contain the homeobox sequence, which is shared with all animals that have a body that has a front and back end.

HOX genes occur in clusters on strands of DNA.

HOX and other developmental genes turn on and off in certain parts of the embryo, making a protein that affects development.

Sonic hedgehog is an important developmental gene that is not a HOX gene. It directs the development of the limbs and fins in vertebrates.