Love-hate relationships on a microscopic level

My name is Jenny and I am a developmental biologist. It’s a hopeless addiction, brought about by the awe inspiring process of making a baby. Get you mind out of the gutter! I’m talking about the process by which a single egg cell, fertilised by a single sperm, grows and divides over and over again to make the 100,000,000,000,000 cells present in a human body. What’s more, these cells don’t just replicate but also somehow organise themselves into lungs, a heart, bones, blood, eyes, a brain and much more. The day that I realised that I could get paid to spend my time trying to understand how this happens was the day I felt that I was finally onto a winner.

Last week, around 800 pallid nerds with similar obsessions to mine invaded Cancun, Mexico for the 17th International Congress of Developmental Biology, and I was lucky enough to be able to join them. We heard many talks from incredible scientists such as Nobel prize winner John Gurdon (who I’ve talked about before, in this post), all focussing on how the body puts itself together. Hearing people talk with such passion about the amazing feats of the growing body has inspired me to try something a little different this week. So rather than write another polemic about what’s wrong with the world today, I’m going to tell a story about one small piece of the embryological puzzle. Some days you just need to feed your addiction.

One of the big question marks over the growth of an embryo concerns how the cells all end up in the right places. This starts with the production of enough cells to even have different places to end up in. Once the fertilised egg cell has divided enough times to make a certain number of cells of the same type, these cells split into groups, changing their physical properties in a process called differentiation. These differentiated groups contain cells which are precursors for specific parts of the body.   So, for example, one set of cells differentiates to become precursors of the skin, one group become precursors to the gut, and all the structures that bud off it. These groups of cells then need to move to the correct part of the growing embryo to ensure that the body ends up with skin, or gut, in the right place.

How do the cells know which end of the growing embryo will be the top, or the left? How do groups of cells of the same type know that they should stick together? Once they’re stuck together, how do they know where they should head to? These are the questions being addressed by Roberto Mayor and his lab at UCL. His team have recently uncovered some exciting new discoveries about how cells in the embryo move, which have helped us to understand how the embryo is organised, as well as giving us new information about what happens when these movements go wrong.

The cells that interest Mayor are a group called neural crest cells. They are the ADHD kids of the cell world, full of energy and able to change direction and purpose on a whim. The neural crest cells flow out from the developing spinal cord down each side of the head and neck in streams to end up in many different places in the body, where they make lots of different structures, including, but not limited to, parts of teeth and bones, nerves and ganglia, and glands like the thymus and adrenal. How, the team wanted to know, did the neural crest cells know where to go?

The key to answering this question was found in another cell type, know as the placode cells. These cells are pretty chilled out, the kind that generally like to put up their feet and watch the Tour de France rather than do any moving around. As the saying goes, opposites attract, and Mayor’s team found that the neural crest cells were drawn towards the placodes like a moth to a flame. As the placodes are positioned part way along the route that the neural crest cells need to be travelling down, the result is that the neural crest cells set off down the right path towards their final destination.

In this video, looking at the left hand panel, you can see the green neural crest cells moving through the red placode cells. The other two panels show each cell population separately, in black and white.

Why are the neural crest cells so attracted to the placodes? It’s certainly not their scintillating conversation, or their deep soulful eyes. In fact, the placodes release a chemical called Sdf1 that acts as a chemoattractant, meaning that it’s a chemical (chemo) that the neural crest cells are drawn to (attractant). The team know that the neural crest cells are attracted to Sdf1 specifically rather than another feature of the placodes because the neural crest cells are also drawn to other types of cells that make this protein.

So, the neural crest cells are headed in the right direction. But, as I’ve mentioned, the placodes are only part way along the path the neural crest cells need to take. Based on what I’ve told you so far, you would expect that the neural crest cells and the placodes would meet up and live happily ever after at this halfway point. But this would be disasterous for the growing body, and so a cunning technique is employed to avoid such a fate. Once the neural crest cells get within touching distance of the placodes, these relatively sedentary cells are spurred into action and actually run away from the neural crest. The neural crest cells chase after the placodes once more, but the placodes continue to play hard to get, and thus the neural crest cells are drawn further and further down the path towards their final destinations. Well played, placode cells.

Mayor and colleagues found that before getting involved with the neural crest, the placodes are already making small movements in random directions, but aren’t going anywhere special. The movements they do make are achieved by putting out protrusions, a little like feelers, on the surface of the cell. However, when they make contact with a neural crest cell, they are actively repelled away, by a force called contact inhibition of locomotion. This means that, upon collision with a neural crest cell, the protrusions on the side of the placode cell that makes contact all collapse, and extra protrusions spring up on the opposite side, directing the cell to move away from the neural crest. And so, this love-hate relationship between the attractive placodes and the repellent neural crest results in the migration of two critical cell types to their required destinations within the growing embryo.

I think that this is pretty cool stuff. But more than just improving our understanding of how embryos develop, Mayor hopes that this research may also help us to understand how cancer cells metastasise, and potentially find ways to prevent the cells from moving. This is because the neural crest cells have several characteristics in common with metastatic cancer cells, in particular their propensity for movement. The team showed that if they prevented the placodes from releasing Sdf1, or blocked contact inhibition between the placodes and neural crest, they could stop these cell types from moving in a directed manner – instead, they moved randomly around the area they started in, never making much progress. If similar cues are causing metastatic cancer cells to move, drugs to block these cues may be able to slow or even prevent metastasis.

In this video, the neural crest cells in the top panel are green, and the placode cells in the second panel are red. In the third panel down, you can see both cell types. The nueral crest cells are in hot pursuit of the placodes, which run away. In the bottom panel, the researchers have blocked the chemoattractant signal of Sdf1. Without anything to pull them towards the placodes, the neural crest cells are no longer interested!

This story reveals just one of the many ways in which cells talk to one another to coordinate one of the biggest organisation challenges on the planet, the putting together of the human body. Some of these lines of communication we know, but many more are tales that are still waiting to be told. So, as the congress came to a close and 800 pink and peeling biologists sadly packed up their belongings and headed back into the lab and away from the sun for another year, it was comforting to know that the next amazing microscopic story could be lying just round the corner.

Reference: This data was published in Nature Cell Biology 15, 763–772 (2013).

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