[MUSIC] One of the most interesting phenomena we see happening during the process of development is the fact that in many cases, the same genes that we see making the limb, that we see making the face, that we see making the heart, are used over and over again, just deployed in different areas, in different scenarios. So for example, in insects, it appears almost as if anytime an insect needs to make something that comes out of the body, an appendage, an antenna, a leg, what have you, the same group of genes are deployed to achieve that task. Another very interesting finding that is emerging from the body of research as it stands now, is that the same genes are being used across organisms. They could be separated by millions and millions of evolutionary years to construct aspects of their body that look somewhat similar. So for example, the genes that go towards making an insect leg, many of those same genes are used to make our legs. The limbs of all mammals have the same bones, right? We all have a part up here. We have part up here, and then we have a bunch of bones here that are fingers. And we've known that these bones were the same among different mammals and actually different groups that have limbs, for hundreds of years. The very first anatomists to look at the bones were able to see that there were very strong similarities between the elements of the limb in different mammals, and different forms with limbs. And they were able to say I think that these elements of the limb are the same. However, it's only been much more recently that we have started to realize and have interesting discoveries from the genomes that tell us that the genes that go into making the limbs are, and actually, among organisms, are very much the same. So the same genes that are very important to making our limbs, are very important to making the limbs of the bat, are very important to making the limbs of the possum. And actually, all the way out there, they are very important to making the limbs of an insect. So what we're seeing, what we've known for hundreds of years, is this conservation in form in the anatomies of the limbs. And what we are finding out relatively recently through new scientific discoveries is that the genes that pattern those segments, even within mammals and out to limbs that look very different, such as those of an insect, are largely controlled by the same genes. Most of my research centers on studying how animals get different forms. And one of the genes that we are very interested in in our research is called sonic hedgehog. And for those of you who might be children on the 90s, you might remember the video game Sonic the Hedgehog. And the gene is in fact named after Sonic the Hedgehog. So the story goes that there were three genes within this family, the hedgehog gene family, that were found. And the first one received the name Indian hedgehog after the Indian hedgehog that runs around in nature. Second one got desert hedgehog, again after the desert hedgehog. And then they had the third one, and they needed a name for it. And so they named it sonic hedgehog. Sonic hedgehog has a lot of important roles within the body. It is very important in establishing the limb and controlling what form our limb has. It's also very important in other parts of the body, as well. Sonic hedgehog and the levels at which it's expressed play a large role in controlling, for example, the face and facial morphology, facial form. It also has roles throughout the body in terms of making our neural tube, our spinal cord. And so it has important roles at many places throughout the body. Now that might lead to this question of, well, okay, sonic hedgehog is important to the limb. It's important in the face. It's important, let's say, in the neural tube. How might we expect to see changes in sonic hedgehog, in this gene, that would ultimately lead to changes in the limb? We look across all these mammals. And what I would like to do now is provide you with an example from our research of, in bat and in pig, of how that process, remember the genes that make the limb are the same in all these organisms. How that process of turning the genes on and off and where they're expressed and how much they're expressed, how it has has evolved, how it has changed in order to yield limbs that look very different from one another. So we'll start by looking at the bat. So remember the bat forelimb is a wing. It has these bones that are really elongated, same parts as our limbs, just much longer. And when we look at how the limb develops, the limb first starts developing, of all mammals, starts developing as a little outgrowth off of the body. So it's a little bud, we call it. It looks like a bud. And it then subsequently continues to grow and form all the parts of the limb that we normally think of. Now this limb bud has molecules that are present, these proteins that are present, that are the products of theses genes. And these proteins and molecules interact with one another to determine what the pattern of the limb is going to be, what the form of the limb is going to be. Within the limb, there are two main areas at which these proteins are turned on, are localized, that are really important to making that final shape. So on this figure, there is this blue area at the end of the limb bud, and there's this green area here in the limb bud. And those are those two major areas in which genes that are really important to making the limb are turned on. And so those specific genes, in the blue, it would be the FGFs genes. And in the green portion of the limb, that would be where the gene sonic hedgehog would be turned on. And these genes and these areas interact in order to control what the limb ultimately looks like. So when we look at a bat, when we take bat embryos, and we look at where these genes are turned on and turned off during bat limb development, we see a slightly different pattern in terms of the size of the expression areas of this genes as we do, let's say, in mouse. So in this figure, if this limb on the right is actually what we would see in mouse, this image that I have just popped up for you shows what the limb would look like in a bat. And what you can see, just as a takeaway from this, is that the size, so the same genes are there, that sonic hedgehog, the FGFs, those two single link centers are still there, but their size is different. So within the bat, the size of both of these centers, the amount of protein that's present has increased in the bat relative to a mouse. And we've done some testing and this relates to, again, that overall size of the limb. So the bats make these really large forelimbs that have these really elongated forearms. And what we think is happening is by turning on these genes at a higher level, making more of the proteins that these genes have, it's stimulating an enlargement of the limb as a whole. So that's one example of how we have the same genes, but they are being turned on in different ways to yield a different structure. We see sort of the opposite thing happening within pigs. So pigs have a situation where they have digit reduction. So instead of having five digits like we do, they have really four digits, and actually not all of those four are really functional. So they have two large middle digits and two smaller lateral digits, like so. And what we observe within the pig is that these genes that we know control limb development are, again, there. They're present, they're turned on. But they're turned on at lower levels. Okay, so particularly, this green area of the limb, which is sonic hedgehog. Sonic hedgehog signaling, not necessarily sonic itself, but the signaling of sonic through many genes through that pathway, is turned down. Okay, so there's less of it present, there's less sonic signalling happening. And then also, this blue area of the limb, which is expressing, turning on the FGF genes, actually turns off sooner. So what that means is that those genes that are being expressed there, those genes that are turning on there to make proteins, they turn on at the right time. They're making their protein. Everything's going great. The limb is developing, and what happens is they just turn off earlier, so they stop making the FGFs earlier in the pig limb, than let's say, in the bat limb, in the human limb. And we think that the contribution of these two factors results, again, in less tissue being present and a situation where now you have fewer digits being made. Okay, so these are the kind of changes that we see. Again, the same genes are present, but the levels at which they're expressed, the locations at which they're expressed, differs subtly among species, among mammals to generate the great diversity in mammalian limb structure that we see in nature today. So to summarize, what some of the big findings that are coming out of our lab. It really is this idea that limb evolution and the change of the limbs among mammals into this diversity of forms that have allowed mammals to be so very successful, that it's really driven by, not by changes in the specific genes that are present within the limb. All of them have the same genes. But it's the relative amounts of gene product that are there, the relative timing of when the genes are turned on and turned off, that are yielding, that are resulting in these large differences in form that we see among mammals. [MUSIC]
