Why did mice, people and other mammals evolve with modern rib cages instead of sporting snake-like ribs that extend from the neck to the tailbone? Ask geneticist Mario Capecchi at the University of Utah in Salt Lake City.
"Mice have long tails so their ribs go even further," Capecchi recounted "If you look at evolution in very early vertebrates, the first ones who came on land were the amphibians. They actually had ribs all the way down their body. But once the mammals started to adapt to land, they wanted to move much more flexibly, faster. Predators were chasing them, perhaps people too. So they wanted to get out of the way. Having all of those rows of ribs made the body fairly awkward. So a body plan was needed to eliminate those ribs you didn't need. In this case, Hox eliminated those from the body.
"Hox stands for homeodomain box,'" Capecchi explained. "That's a DNA binding motif. All of these are transcription factors, and each one turns on 100 other genes. So Hox genes are the major regulators of body plans. They orchestrate the activity of other genes to make an embryo develop into an adult. The same genes that make a body axis also make limbs. Hoxes evolved to make the four principal elements of limb bones: the humerus, the radius, the ulna and the bones of the hand. And the significance there is that 1 percent of kids are born with limb defects. And eventually we want to be able to do something about that. But first we have to understand all the details involved in making these elements."
Global Patterning, Not Local, Is Hox Gig
Capecchi, an investigator at the Howard Hughes Medical Institute, is senior author of a paper in the current Science, dated July 18, 2003. It's titled "Hox 10 and Hox 11 genes are required to globally pattern the mammalian skeleton."
"The take-home lesson of our finding," he observed, "is that first of all, the Hox genes are involved not in localized patterning of these specific vertebrae but rather global patterning. We're distinguishing whether Hox genes are individually modulating each vertebra or whether a particular set of Hox genes are involved in saying, Make this many thoracic vertebrae, make that many lumbar.'
"If you look at different spinal columns," he continued, "some have five thoracic vertebrae, some have six, some have 14. We humans happen to carry 12, mice 13. And if we inactivated in humans all 10 paralagous members, instead of having 12 ribs, now we would probably have over 24 ribs. You'd be making ribs all the way down to your tail. Humans have a very short tail of just a couple of vertebrae.
"From individual Hox mutations it was clear that they were involved in doing something in making the body plan - the main skeleton. But it wasn't clear how, because individual mutants would change one vertebra, one way or the other way or a third way. So, from looking at individual mutants it wasn't clear what they were doing. And now, when we put them all together, all of a sudden it's clear. That's the novelty.
"There are three members in each of the mammalian Hox gene families, and two alleles - one from the mother and one from the father - of each mouse chromosome. When we inactivated five of the six we still didn't see it. It took disabling all six to see what was happening. Doing early vertebrate phylogeny in evolution led to the quadruplication of these complexes. They retained their original roles but also gained new roles.
"Hox genes have been known to science for exactly 20 years," Capecchi recalled. "But because they still retained their old habits, we had to inactivate them all before we could see what all of them were doing. Now they number 39 separate genes, in all mammals, including mice and humans. There should have been 13 gene families, and four of each, so there should be 52 in all, but some of them aren't needed. Therefore, they were lost during evolution, paring it down to 39, which are still used. Each of them does very different things. We've inactivated all of the 39 in mice to study. For example the two that we're working with also involved organogenesis - making kidneys. Some of them involve brains."
Hox Brain: Obsessive Compulsive Disorder
"There are sporadic mutations as well," Capecchi continued. For example, we manipulated some that are involved in making hands. Comparing murine and humans, they have very similar defects in their hands, due to sporadic mutations. They would have a defective hand. Right now we have a Hox gene that looks as if it gives the mice OCD - obsessive compulsive disorder. So now we're going to the human population and ask whether patients with OCD have mutations in their teeth and we're just in the process of doing that analysis.
"Patients diagnosed with OCD mindlessly repeat things all the time, wash their hands all the time, so they have lacerations in their hands. In mice their OCD behavior is very similar and the other thing that is very similar is where these genes are expressed in the brain. They're almost identical. These patients and these mice pull out their hair all over their body. Another OCD-related example would be to blurt out profanities like Tourette's syndrome.
"A very common thing with birth defects," Capecchi commented, "is to have extra ribs. For example, if a mother is drinking a lot of alcohol, all of a sudden she has redundant ribs on her skeleton. Why is that?," he asked rhetorically. "And we would say: Hox is probably involved in this particular circuit. Somehow alcohol is upsetting this pregnancy and now she is where she shouldn't be.
"In humans," he pointed out, "it's only a correlation. In mice, researchers have shown that if you give a mouse a lot of extra alcohol, predictably it affects the ribs. It is known that humans do have extra ribs; in mice if you give them extra alcohol at the right time in pregnancy they develop extra ribs."