Good Fences Make Good Neighbors

Ephrins are cell surface receptor-ligand pairs that create boundaries throughout the body.

Ever wonder how organs form and stay distinct? All our DNA is the same, yet the cells it gives rise to differentiate, migrate all over the place, through each other's neighborhoods, and then form various distinct tissues, including 700 unique muscles. Cells don't have eyes or brains, so the mechanism is more like ants following pheromone trails rather than an architect following a masterplan of the body. It is a far more complicated story than anyone understands at the moment, but some of the actors are known.

There are a lot of cell adhesion proteins, such as integrins, cadherins, NCAMs. and selectins. But adhesion can't be the whole story, lest every cell adhere to every other. That is where Ephrins come in, which are a family of cell surface molecules which typically have repulsive effects, when they find and bind to their receptors (called Eph). They are widely used in development and mature tissues to keep proper boundaries and help guide that way for migrating cells and cell processes.

It has long been known that if you dissociate embryonic tissue and allow the cells to float about, they will re-associate in an organized (though far from perfect) way, like sticking to like, with boundaries forming between those from different tissues. This indicates the power of selective adhesion and repulsion to help cells position themselves, which operate in conjunction with other systems that keep their identity straight- what organ or tissue they are supposed to be. Each such cell type expresses its own complement of adhesion and repulsion surface molecules, forming part of the code that helps it to find and keep its place, as well as deciding whether to continue dividing and moving, or to stop when the local structure has reached its expected proportions.

On the left, one tissue expressing an Eph receptor keeps separate from another tissue expressing the  Ephrin ligand which it recognizes, thanks to repulsive effects that counter-act several other adhesive interactions. On the right are a few of the details of the mechanism. Each side of the Ephrin-Eph interaction can tell its cell that an encounter has happened.

These mechanisms take another quantum leap in the nervous system, which involves a particularly high level of cell migration during development, and pathfinding of dendrites and axons throughout life. Axons travel huge distances, both in the central nervous system and in the peripheral nervous system, using adhesion and repulsion cues all along the way. Ephrins are used dynamically to guide growth cones. For example in the serotonin network, serotonin neurons traveling from the dorsal raphae (B7) to the forebrain olfactory bulb pass by the amygdala. Do they stop there to extend some input fibers? Normally they do. But not if the amygdala has been genetically altered (in these mice) to express the EphrinA ligand, which pairs with the EphrinA5 receptor that is normally expressed on these neurons.

EphrinA is typically expressed in the hypothalamus, keeping serotonergic projections from the dorsal raphae (on the left, B7) from innervating. But if it is expressed (in mice) in the amygdala, it prevents that normal innervation as well, as these neurons travel during development into the forebrain, in this case the olfactory bulb (OB).

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