Axonal Guidance Cues and Target Selection in the Developing Cochlea

With the addition of new molecular and genetic approaches and the potential for hair cell regeneration, investigations into the development of the auditory system have taken on added significance. Such investigations are elucidating the general principles of how intrinsic genetic programs operate in conjunction with external factors. One such general principle is that intercellular communication and the temporal expression of cellular signals are essential to the survival of both neurons and sensory cells. The survival of neurons is related to their connections with sensory cells, so the loss of receptor cells can result in the loss or redistribution of auditory neurons throughout the auditory system.[1] In the mammalian cochlea, our studies suggest that the expression of synaptic proteins and certain extracellular matrix proteins coincides with innervation by brainstem efferent neurons.[2] [3] During development, efferent innervation appears to be relatively independent of neurotrophin-guided signals. Although hair cell maturation is morphologically independent of efferent innervation, the timing of efferent synaptogenesis is an important precursor to outer hair cell (OHC) motility and may be important for some aspects of inner hair cell (IHC) function. Expression of the molecules necessary for efferent function or for OHC motility is developmentally regulated and occurs around the time of efferent innervation. In the embryonic and postnatal rodent cochlea, we have evidence that efferent axons form transient connections with IHCs on their way to form synapses with OHCs. Nicotinic acetylcholine receptors are expressed by IHCs just prior to the arrival of efferent axons and then by OHCs around the time of efferent innervation.[3] [4] [5] The idea that the early presence of cochlear efferents plays a role in the normal maturation of afferent responses is supported by observations of abnormalities following ablation of the efferent projections as well as by studies of IHC responses to acetylcholine.[6] [7] The mechanisms by which both afferent and efferent neurons connect to hair cells remains unresolved.

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