Lateral line sensory nerve guidance by a migrating cell collective

PROJECT SUMMARY The cochlear nerve, critical for hearing, relies on precise extension and connectivity during development. Cochlear nerve deficiency (CND) is a congenital malformation resulting in an absent or small cochlear nerve that leads to severe or profound hearing loss with permanent and detrimental effects on patient quality of life. To better understand CND pathophysiology, the mechanisms guiding cochlear nerve development must be understood. This project’s objective is to determine how the in vivo tissue environment impacts cochlear nerve development, using the zebrafish posterior lateral line nerve (pLLN) as a model. Similar to processes in the mammalian cochlea, the zebrafish pLLN extends alongside a migrating cell collective called the primordium. Our hypothesis is that secreted signals from the primordium contribute to the dynamics of adhesive signaling in pLLN development. These mechanisms will be investigated in zebrafish by integrating in vivo imaging of fluorescently labeled growth cones and primordium cells with genetic and experimental manipulations. In Aim 1, the role of specific adhesion molecules in the co-migration of the pLLN and primordium will be characterized. Aim 2 will examine how the location and timing of secreted cues impact pLLN extension and adhesion to the primordium. Lastly, Aim 3 will focus on mapping the progressions in gene expression of neurons forming the pLLN and the cells of the primordium over time as a way to evaluate the relative composition of intercellular signaling. These studies will clarify how adhesive and secreted cues cooperate to ensure robust pLLN development, offering insight into the developmental process of the cochlear nerve. Findings in these areas support the search for future therapeutic targets for CND. The described studies will be carried out under the direct mentorship of Dr. A. J. Hudspeth at The Rockefeller University within the supportive Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program environment. This fellowship constitutes an important career milestone for dual-degree students seeking to become independent investigators.