Saturday, May 2, 2015

Do Neurons Use GPS?

No, neurons and their axons use chemical guidance signs to find out where they should be going, in huge migrations though development.

The brain and nervous system don't just happen by way of cell division during development. They are products of enormous migrations from points of cellular birth, which are generally at the edges of the nascent structure, such as the ventricles of the brain. And getting the cells to the right place is only half the story, as neurons then send their axons all over the place as well, to create those amazing connections that run our bodies and minds. Neurons that enter our feet typically have their cell bodies at the base of the spinal chord and send axons along a tortuous path that of course ends up going about three feet in adults. It is astounding.

Some of our neurons are very long, and for most neurons, their axons as well as cell bodies migrate substantial distances during development.

Obviously, the mechanisms behind these movements are going to complex. One example is in the brain, where new neurons travel out to the various layers they are destined to inhabit via a scaffold of guide cells, the radial glia. Even when such physical structure helps out, the primary mechanism is a sort of pheromone system, like what ants use when making trails, but a good deal more involved. A recent paper describes the chemical signals that guide neural axons of the mouse through a critical crossing at the midline of the spinal chord.

These axons are called "commissural axons", since they cross the bilateral joining point, or commissure between the two sides of the body. In the brain, the corpus collosum is a large bundle of such axons.
"For example, commissural axons are initially repelled by bone morphogenic proteins (BMPs) in the dorsal half of the spinal cord. They are then attracted by gradients of Netrin-1, Sonic hedgehog (Shh) and vascular endothelial growth factor (VEGF) towards the floor plate."

The floor plate (bottom) secretes two molecules, Shh and Netrin, in wild-type mammals. If either one is mutated and absent, neurons that normally use gradients formed by those molecules to know where they are going do not find their way as reliably.
"While it is known that both Shh and Netrin-1 form gradients, it is not clear how steep the gradients are in vivo and how this steepness influences axon pathfinding in gradients formed by single or multiple guidance cues. Although theoretical chemotaxis modeling has suggested that two overlapping attractive concentration gradients could increase the probability of a cell making a correct decision about the gradient direction, this prediction has not been tested experimentally."

The "pass" from one side of the spinal chord to the other, at the early embryonic times when this axon extension process takes place, is called the floor plate of the neural tube. It is the site of expression of at least two guidance molecules, the proteins Shh and Netrin. These are secreted and form a gradient that is sensed by receptor proteins on the axons, specifically by their pseudopod-like front end called the growth cone. One trick is that once axons find their way to the floor plate, they need to reverse their response pattern so that they grow away from it instead of towards it. This repulsion from the floor place is known to be mediated by another molecule, Slit.

But that is not the topic of the current paper, which simply makes the observation that for the attraction phase of axon growth, two signals is better than one. This has been presaged by mutant studies where the mutation of each individual gradient attractant, Shh and Netrin, causes worse axon guidance, but not a complete breakdown of commissure formation as happens when both are deleted (see figure above).

Neural growth cones seen in the process of deciding where to go. Gradients are indicated by the black triangles at sides, as set up in the lab. "A" presents a schematic of a growth cone showing asymmetry of the protein signaling kinase SFK, which accumulates internally on the more highly stimulated side, reflecting part of the cell's mechanism for detecting the outside guidance molecule signaling gradient. SFK responds to both Netrin and Shh.

The researchers take this all in vitro, reproducing the gradients with microfluidic cells, and asking how their cultured neurons move in response. They find that, as expected, gradients that are shallow as they are in the embronic setting where the axons spend most of their time are not very good at guidance for each molecule individually.

Summary of experiments, showing both axon migration (the cell bodies are dots, and the axons lines) and SFK kinase orientation within growth cones, all responding to the combination of two shallow signaling gradients more reliably than to either alone.

They also show that within the guided growth cone, a key protein (kinase) that transmits the Netrin and Ssh signals from outside to inside itself adopts a biased concentration gradient, matching what is detected outside. Aside from validating the other findings, this provides some rationale for large sized of growth cones, which by spreading out physically can detect relatively shallow gradients of their signalling molecules.

It is not a momentous paper, but a small step on the way to learning how the nervous system develops ... from one cell to the most complicated machine in the universe.



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