In this system, as in others that we have mentioned, the repulsive interactions are mediated by ephrin–Eph signaling—specifically, EphrinA–EphA signaling for the anteroposterior axis (Figure 21–79). An analogous mechanism based on EphB–EphrinB signaling orients the dorsoventral axis of the retinotopic map.
These mechanisms serve to orient the map along both axes, but they are not enough by themselves to ensure accurate point-to-point detail. This is brought about through a long process of adjustment that fills in and refines the map through interactions among the RGC axon terminals as they compete for territory on the tectum. This refinement of the pattern of connections involves electrical signaling in the system of developing synapses—a topic that we return to shortly.
Both Dendrites and axonal Branches From the Same Neuron avoid One another
Axons and dendrites from different neurons can repel one another, or they can cohere; they can collaborate to form synapses, or they can compete. Remarkably,
Figure 21–79 Ephrin signaling orients the retinotopic map. (a) Neurons in the posterior retina express epha. as their axons reach the tectum, they are repelled by high levels of ephrina protein in the posterior tectum and project preferentially to the anterior tectum. (B) In epha-mutant mice, posterior retinal axons feel no such repulsion and project more widely within the tectum. (after e. Kandel et al., principles of Neural Science, 5th ed., New York: McGraw hill Medical, 2012.) axons or dendrites can also repel each other when they arise from a single neuron. Such self-avoidance prevents the neuron from making purposeless synapses with itself; it also helps the cell spread out its processes widely so as to innervate a broad territory.
Self-avoidance poses a problem. If the same self-recognition molecule were used in every neuron, all neurons in the brain would repel each other. Some classes of neurons do show this sort of mutual repulsion, creating solitary territories—a phenomenon called tiling; but in most cases, axons and dendrites from different neurons can overlap with one another. How then can the processes put out by a single neuron distinguish between self and non-self? This conundrum has been partially resolved by the discovery of a remarkable set of proteins that endow each neuron with a label unlike that of its neighbors. These are the DSCAM proteins in Drosophila and the protocadherins in vertebrates. As described in Chapter 7, DSCAM proteins are extraordinary for the number of isoforms that can be generated by alternative RNA splicing—more than 30,000 variants for DSCAM1 (see Figure 7–57). Diversity arises from alternative exons that code for three highly variable extracellular immunoglobulin domains. Each DSCAM1 isoform engages in homophilic binding (see Figure 19–5), but remarkably, all the variable domains need to be identical for this to occur. Thus, one cell surface will bind to another via DSCAM only when the two cell surfaces express identical isoforms. The result of binding is repulsion, although the detailed mechanisms are poorly understood.
If alternative splicing occurs in a random fashion in each cell, neighboring processes from different neurons are unlikely to express the same DSCAM1 variant, so only the processes of the same cell will repel one another. Neurons that lack all DSCAM1 variants have severe defects in neuronal self-avoidance. Engineering Drosophila so that all of its neurons produce a single isoform restores self-avoidance; but now the processes of neighboring neurons express the same isoform and repel each other, resulting in the phenomenon of tiling (Figure 21–80).