Genetic basis of intrinsic and extrinsic contributions to the establishment of muscle pattern in the developing limb

点击翻译按钮获取中文摘要

If you open a book showing the inside of the human body one of the most striking things is how the tissues and organs are present in the right place and at the correct shape and size. One of the questions that we want to find the answer to is: how do tissues and organs develop in this way? We know that this is controlled to an extent by genes, because mutations, which cause genes to be defective, can make tissues and organs to develop abnormally. We are looking at how the muscles of the body develop in the embryo. The human body has about 650 muscles, some muscles are very large (in the leg), others are very small (in the eye). We know that each of the 40 muscles in the arm has a particular place, and it is connected by tendons to particular places on bones at each end. Because this is the same in different people, we can give a name to each muscle. The question we ask is: how does this happen? For the muscles of the arms and legs this is particularly interesting as these muscles have the strange behaviour in that they grow from muscle cells that move into the arm or leg as the embryo develops. How do these muscles know where to go in the limb and make a particular muscle, why don¿t they get all mixed up and make a jumbled muscle, and how do they make the specific attachments to bones? There are different possible solutions to this problem. One way might be that the muscle cells are programmed to know where they have to go. This is like going for a car drive and you know where you will be going and the route you will take before you start. Alternatively, muscle cells may have no clue where they are going but just follow the directions they are given. This is like a train that can go forwards, but where it goes depends on the train tracks and signals being set correctly by someone else. Scientists think that the train on the tracks model probably is a better explanation of how muscle cells move to their correct locations, and cells in the limb give signals to the muscle cells such as: move here; don¿t go there; keep moving; stop now; make a muscle now. But this is not 100 per cent certain. We wish to do a project to look into this and see if we can find some answers. We shall use a mutant mouse that has a mutation in a gene that makes a protein that switches on other genes. It is what we call a regulator gene. Mice which have a mutation in this regulator gene have very peculiar problems in the way muscles in their arms and legs form. We have noticed that some muscles are completely missing, other muscles form in places that they should not, and some muscles although they are in the right place have split into two muscles. On top of this we have seen that the tendons of the muscles are also abnormal, and many of them are much smaller than normal. We want to find out if these muscle problems are because the muscle cells that make this muscle are defective in their programme (as if some of them cannot read the road map correctly), or is this because the tendon cells and others which may signal to the muscle cells are defective (as if the switches on the rail track have been left in the wrong position, so the train goes in the wrong direction).