Why do we care?
In Hirschsprung’s disease, which occurs at 1/5000 live births, the cells don’t make it to the end of the intestine. This means that there is a section at the end of the intestine without nerve cells, so food can’t get pushed all the way along and out of the intestine. This is a serious disease that can be fatal if untreated, so it is important to understand how it occurs in order to prevent it.
What do we already know about enteric neural crest cell migration?
1. There is no fixed migration direction: Colonisation of the gut always occurs in one direction. However, when cells are implanted into the middle of the gut, they migrate in both directions. This suggests that the normal direction of migration is not due to something within the neural crest cells or the gut, but simply because the cells always start at the stomach-end of the gut and only have one way to can go.
2. There is a maximum density of cells: No matter the initial number of cells, the density of always ends up the same. This implies that cells keep proliferating until the maximum density is reached.
3. A certain population size is required: When cells at the front of the migrating population are separated from those behind them, their rate of migration is reduced. This suggests that the cells are “pushed” from behind by other cells. If so, an adequate population size is required for the leading cells to maintain the right speed to get to the end of the gut.
What does this study investigate?
Simpson and colleagues wanted to find out how these cells travel such a long distance. They suggest four potential models:
1. Leapfrog: Leading cells stop migrating when they find a good spot and those following overtake them. They in turn stop migrating when they come to an empty section of the gut, and so on.
2. Mixing expansion: All neural crest cells proliferate and migrate forwards, swapping neighbours as they go. Any cell can end up and the front or the back of the population.
3. Shunting expansion: All cells proliferate and move forward, but they tend to keep the same neighbours. Cells that start at the front stay at the front.
4. Frontal expansion: Leading cells keep proliferating and moving forward, leaving a trail of immobile cells behind them.
Their study also investigates whether a mathematical simulation can help to answer their question. Other studies have already discovered many factors that are important in enteric neural crest migration - genetics, molecular interactions, cell movement, cell-cell interactions, and so on. The next hurdle is to combine individual bits of information from the genetic, molecular, cellular and tissue levels to understand how the entire system works. To do this, the authors create a mathematical simulation and compare it to their experimental results.
Can the mathematical simulation make accurate predictions?
They created a simulation that mimics “normal” neural crest migration and test it by asking it what happens when cells were put in the middle of the gut. We already know that the cells will migrate in both directions, and this is also what the mathematical simulation predicts. So far, so good.
Do cells from the front migrate when they’re put at the back? Can cells from the back colonise the gut?
Next they start testing their models. The mathematical simulation suggests that cells put at the back of the population will not be able to migrate, presumably because other cells are in the way, and will also not be able to proliferate, because cell density is already at capacity. The experiment gave the same results.
This begins to cast doubt on the leapfrog, mixing expansion and shunting expansion models, all of which predict that cells at the back can move forwards. To investigate further, cells from the back were moved to the front of the cell population. These cells were able to move forward a huge distance - much further than cells put at the back of the population. It seems that cells from the back have a similar migratory potential to those at the front and this suggests that cells at the back and the front are identical - they simply end up in a certain position by chance. From these results, the researchers conclude that the frontal expansion model is the one that best explains the mechanism by which neural crest cells colonise the gut.
What keeps cells in their place?
Finally, they test the importance of proliferation by putting donor cells at the front that were unable to proliferate. They suggest two possible outcomes for this experiment - these cells might be pushed forward by the cells behind them; or, they might get in the way of those behind them. Mathematical simulations suggest that, if leading cells aren’t able to proliferate and increase cell density, some other cells will eventually be able to overtake them and colonise the gut. The experiments completely agree with the mathematical simulation, providing further evidence that the frontal expansion model is correct - or, at least, is the best model we have for the moment.
#developmentalbiology #neuroscience #cellbiology
Simpson, M. J., Zhang, D. C., Mariani, M., Landman, K. A. and Newgreen, D. F. (2007) Cell proliferation drives neural crest cell invasion of the intestine. Developmental Biology 302:553-568