Signal Corps -
March 5th, 2014
We have discussed protein synthesis, protein trafficking, vesicles and their cargo and signal transduction. We now know that generating and receiving protein signals allows cells to coordinate their differentiation and behavior across distances and is absolutely critical to our normal development and health. There is a structure in the cell that seems to be a signal center for this activity and it utilizes all of the parts of the protein story we have discussed. This structure has been recognized for more than 100 years but largely ignored until recently. The interest now is because of the discovery that it sends and receives signals critical to pattern formation (our development; the making of brains, hands, feet, hearts and the other bits that make us who we are). The structure is called a primary cilium and it looks like an antenna on the surface of the cell.
Very highly magnified picture (from an electron microscope) of a cell and its primary cilium. With permission from the Gleeson lab http://www.cbd.ucsd.edu/
Remember we discussed how the cells of organisms today had many components that came from ancient organisms that tried to eat each other! The ones that survived had parts of both organisms. That is why our cells have a nucleus and mitochondria. Flagella or cilia are important parts of cells, which are little tail like structures that whip around and can move the cell. Sperm cells have a really good one that zips those little guys straight to their target. Margulis argued that spirochetes (wiggly bacteria) were the origin; they can move rapidly around their environment also. This idea has not gained a lot of support and perhaps some other flagellated bacterium was the source after some ancient cell made a meal of him. Others think that flagella (cilia) arose in cells from the apparatus that helps cells divide (we will explore this amazing phenomenon at a later time). Primary cilia are very similar to these other tail-like structures except they don’t move.
A conveyor belt of buckets called intraflagellar transport (IFT) carries proteins into and out of the primary cilium.
As a structure they are ideally suited for sending and receiving protein signals. They extend into the environment surrounding the cell and can sense what is around, they are long and skinny so they have lots of surface area to interact with signals through membrane receptors, and finally there is limited access of proteins to the structure making regulation easier. This last one is really interesting. Proteins are not made in the cilium; they need to be moved into it. This is done with amazing machinery called Intraflagellar Transport proteins (IFTs for short). These work like those great kids toy conveyer buckets to move specialized signaling proteins into and out of the structure.
Sonic hedgehog (Shh) makes the membrane receptor patched (PTCH) move into the cell in a vesicle which allows the membrane protein smoothened (SMO) move up the cilium. Then IFT moves an active GLI molecular switch out of the cilium allowing it to go to the nucleus and turn other genes on or off. Figure modified from one provided by Chris Chandler.
In an earlier post we discussed signal transduction, a process whereby a proteins outside the cell would control what genes were turned on or turned off inside the cell. A great example is a protein called Sonic Hedgehog (read our post about gene names). This is a very important signal that prompts the correct development of fingers, toes, limbs, the brain and spinal cord and bones among others. It does all this by controlling gene expression, that is, which genes are on and which are off in a given cell. To do this it reacts with proteins in the membrane. First it sticks to a receptor called patched. When it does this the Sonic hedgehog-patched complex moves into the cell in a vesicle. This separates it from another membrane protein call smoothened. Then little molecular switches, transcription factors called GLI (because they were discovered in a human brain tumor, a glioblastoma) become active and move to the nucleus to control expression of other genes. All this activity occurs at the primary cilium, our antenna! The GLI transcription factors are found at the tip of the primary cilium and get there with the help of the IFT conveyor belt. Since the GLI proteins in normal cells are not in other parts of the cell there is no point in having ribosomes make it everywhere in the cell. Translation of the GLI messenger RNA is prevented by another protein called Quaking that sticks to one end of the RNA. Amazing!When all this works we get normal development…and most of the time that is exactly what happens. When it doesn’t work the result is terrible birth defects or even cancer.The primary cilium facilitates the work of many other networks of genes and proteins like Sonic hedgehog and together they ensure that key proteins are made at the right time and place so that cells can develop normally producing our tissues, organs and structures.
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Originally published at lcresearchcenter.tumblr.com.
