Target Specificity and Its Role in Development and Evolution

The task facing the nervous system during development is largely one of population matching: neuronal input populations must find the correct target populations, and form the correct number of synapses, in the correct position, within each target (Katz and Lasek, 1978). Molecular guidance cues are responsible for many aspects of target specificity, but, given the impossibility of prespecifying every connection genetically, some general rules are enforced instead. Target choice occurs in a hierarchical fashion and is not absolute. Targets apparently possess labels that are recognized by their usual input population, but if that target population is missing, other target choices are possible, with some preferred over others.

1.10.3.1 Population Matching in the Retinotectal System

Like many central sensory brain structures, the optic tectum (also known as the superior colliculus (SC), in mammals) contains a map of visual space conferred on it by the orderly projection of retinal ganglion cells. In amphibians, if an eye is surgically rotated and the optic nerve allowed to regenerate, the retinotectal projections grow to their previous termination sites, suggesting that the regenerating retinal axons follow pre-established chemoaffinity markers in the tectum (Sperry, 1963). This suggestion was supported by observations that, if half of the tectum is removed, it is initially innervated only by the corresponding half of the retina (Attardi and Sperry, 1963). With time, however, the map regulates such that the retinal axons fill the remaining target space, creating a compressed retinotectal map of visual space (Schmidt, 1982). The same regulatory process occurs during development in rodents; removal of part of the SC in neonatal hamsters results in orderly compression of the retinotopic map on to the SC fragment (Finlay et al., 1979; see Goodhill and Richards, 1999, for review).

1.10.3.1.1 Role of ephrins in retinotectal map formation A large body of research points to the ephrins and the Eph tyrosine kinase receptors as the molecules responsible for chemoaffinity in the retinotectal projection (Drescher et al., 1997; Flanagan and Vanderhaeghen, 1998; Frisen et al., 1998; O'Leary and Wilkinson, 1999; Knoll and Drescher, 2002; McLaughlin et al., 2003). EphA receptors and ephrin-A ligands are distributed in opposing gradients, with ephrin-A expression high in caudal tectum and EphAR expression high in nasal retina (Figure 1). Binding of receptor and ligand results in growth cone collapse, and thus the anteroposterior axis of the retinotectal map is built by repulsion of incorrect terminations. Knockout of ephrin-As leads to severe disruptions in map topography, in particular caudal overshoot of retinal axon targeting (Ciossek et al.,

Retina

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