Wouldn't we all like to know how to control hairiness? Women complain that they have too much, and spend half their lives eradicating the little bastards. Men have too little on the tops of their heads, and, let us say, carpets in other places. Well the molecular pathway that regulates hair density has been established. (Is there anything science can't do? I will answer. No.)

Setting aside for a moment the issue of putting this information to medical use, the issue of how hairs are created can also be generalized into one of the great problems of molecular biology: how to take a homogenous surface of cells and turn them into a heterogeneous collection of functional units?

In this case, the problem is how do you take a sheet of ectoderm and create a hair here and a sweat duct there and plain old epidermis there? This may seem rather pedantic, but it is a big problem when you remember that each hair cell is not a homunculus. It has no idea whether the cells right next to it are becoming hairs or not. There is no overarching force that is determining the hair count. It has to emerge from the bottom up.

One of the techniques that is used consistently in biological systems to solve this problem are so-called Activation-Inhibition systems. Here is a description of them from the paper we are going to talk about:

Periodic patterns are a recurring theme in anatomical organization. Examples in diverse organisms include insect bristles, mammalian hairs, the location of leaves on a plant, and the location of stomata on those leaves. In all of these cases the position of each element in the pattern is defined relative to the others rather than to an absolute anatomical location. With regular patterns found so widely in nature, a key question in developmental biology is how an ordered array of structures can be generated from an initially homogeneous field of cells. In general terms, such patterns can be generated by using two signals with different ranges of action. These activation-inhibition systems rely on an activator that promotes (i) its own synthesis, (ii) assumption of a given cell fate, and (iii) synthesis of an inhibitor of this fate. Crucial in generating a spatial pattern is that the activator acts locally, whereas the inhibitor acts at a distance from its site of production. These types of molecular interactions are predicted to be capable of generating a periodic pattern by amplifying stochastic asymmetries in initial concentrations of activator and inhibitor. (Citations removed)

An activation-inhibition system works something like this. Take a sheet of cells with varying levels of a receptor that triggers the development of a particular cell type. If the sheet is from a common origin, each cell in it will express about the same amount of receptor but not exactly the same because that level of perfection is not attainable in biological processes. Then. you make the receptor activate its own creation, and you make the activation of the receptor secrete a molecule that inhibits the same receptor at a distance.

I know that your gut instinct is telling you that "Hey, it activates itself but also inhibits itself. What gives? Wouldn't nothing happen?" The answer is no, and the reason is the distribution of receptor at the beginning is subtly nonuniform.

Instead, what rapidly emerges from something like this is a punctate distribution of the receptor in what was a homogenous sheet of cells before. The reason is that by acting recursively the receptor increases its own expression in places where it is already slightly higher. These places in turn secrete inhibitors that suppress this production in neighboring cells. Therefore, the process of selecting where hairs are going to be becomes a stochastic competition -- I can't tell you which cell will be a hair but I can tell you the rough concentration of them.

Mou et al in PNAS show that a system like this one is functioning for the creation of hairs. The receptor in this case is called Edar. It is activated by a ligand called Eda (they show that this ligand is dispensible because if you overexpress Edar you can get hairs without it, but I don't want to go into that detail). The inhibitory signal that goes out from the cells is called BMP.

Just to visualize it here is a figure from the paper (click to enlarge):

Part A of the figure depicts the embyronic skin, and the expression of Edar at an early date and at a later date. See how the homogenous expression of the receptor changes to a punctate distribution. They know that Edar is responsible because in a mutant shown below that lacks a key protein in Edar signaling (Edaradd), the punctate distribution doesn't form.

Skipping B, you can see in C that another molecular marker of hair formation, Shh, increases in the density of follicles points as the amount of Eda increases. In fact, if you get too much Eda -- by not removing it from the skin ahead of time and then adding more -- the skin tries to form into one big follicle. This increase in density is shown in graphical form in D.

Moving to this issue of the inhibitor the slide below shows that BMP suppresses the hair formation (click to enlarge):

So ladies and gentlemen, we know our enemy, and its name is Edar. Edar signaling holds the key to all your hairiness dreams and woes. But even more than that this is a very good example of how in biology general principles of organization are exploited over and over again to accomplish specific developmental tasks. This idea of activation and inhibition created heterogeneous distributions out of a homogenous substrate occurs everywhere in biology. The next time you see a system like this, try to think of the general principle that underlies it.