The role of Eph/ephrin interactions in the development of inner ear innervation

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The inner ear is a highly complex architectural and functional structure that is exquisitely organised to detect sound and movement, yet it develops from a simple sheet of epithelial cells. During development this epithelium must generate and organise all of the major cell types found in the mature organ, including the specialised sensory hair cells that detect the sound or movement, the non-sensory cells that support sensory cell function and the neurones that connect the organ to the central nervous system. The sensory cells detect the sound or movement stimuli and convert these into signals that are sent to the central nervous system via neurones. It is only when these signals are processed in the brain that they are perceived as sound or movement. Thus, the development of the neuronal connection between the inner ear and the central nervous system is crucial to the function of the inner ear and the perception of sound and movement. The generation of neuronal precursors is an early event during the development of the inner ear. Within the simple epithelial sheet a population of cells begin to develop as neurones. They migrate out of the epithelium into the surrounding tissue where they coalesce to form the cochlear-vestibular ganglion. Subsequently, they produce processes that grow back into the epithelium to connect to the sensory hair cells and towards the auditory and vestibular centres in the central nervous system. These events require dynamic changes in the cell-cell interactions that drive their release from the epithelium, support their migration and direct the growth of processes to the correct targets. Cellular interactions are controlled by numerous cell surface molecules that send signals into the cell when they bind to surface partners (ligands) expressed by neighbouring cells. The cell signalling results in changes in cell behaviour by, for example, causing the cell to be attracted to, or repelled from, the source of the ligand. One such family of cell surface molecules are the Eph receptor tyrosine kinases (Ephs) and their ligands the ephrins. Interactions between these molecules have previously been shown to have important roles in the organisation of the nervous system but their role in the early development of inner ear innervation has yet to be investigated. The aim of the work proposed here is to better understand the role of Eph/ephrin interactions in the development of inner ear innervation. We will focus on two events: first, the migration of neuronal precursors out of the early inner ear epithelium and second, the early growth of neuronal processes. To address these questions we will further develop an otic epithelial explant system that is currently being used in the lab in order to allow manipulation of the expression of Ephs and ephrins. The effect of changing the expression of these molecules on neuroblast migration and process formation will then be monitored in culture using timelapse microscopy and immunohistochemistry. These experiments will further our understanding of neuronal development of the inner ear and other organs derived from epithelia, such as the olfactory system. The development of a novel technique to manipulate expression of important molecules within a developing organ in culture will facilitate future studies into the development of these organs. In addition, these experiments will aid research into nerve regeneration following damage and potentially influence the development of cochlear implants by elucidating potential strategies to encourage neural growth towards implant electrodes, thereby, enhancing the implant performance.