Non-sensory cells as a potential source for signaling molecules in the cochlea



 DESCRIPTION (provided by applicant): The sense of hearing depends on the perfect function of the cochlea, which is a highly organized structure made up of a wide array of cell types. Although hair cells are the primary detectors for sound, many other cells influence how wavelengths of sound travel through the cochlea and also establish the unique environment that is critical for hair cell activation and transmission of signals to spiral ganglion neurons. Hence, mutations that prevent the normal development or function of cells outside of the organ of Corti can also cause deafness, as exemplified by the prevalence of connexin-26 and pendrin mutations in the human population. Understanding how each of the specialized cell types in the cochlea develops to achieve its mature function will elucidate the diverse origins of deafness and improve methods of treatment. Among the least studied cells of the cochlea are the non-sensory cells that populate Reissner's membrane, the spiral limbus, and stria vascularis. To date, we know very little about how the early non-sensory epithelium is patterned to produce different types of cells, let alone how non-sensory cells might influence other cells in the cochlea. In fact, a number of secreted proteins, including neurotrophins, are produced by non-sensory cells, both during development and in the mature cochlea. We find that the secreted protein Netrin-1 (Ntn1) is produced by non-sensory cells in the roof of the developing cochlea. Surprisingly, extra neurons develop outside of the cochlear duct in mice completely lacking Ntn1 activity. Further, we discovered that non-sensory cells can be uniquely defined by expression of the immunoglobulin family member Lrig1. We therefore propose to use Lrig1 as a molecular handle to characterize the molecular and cellular properties of non-sensory cells and to investigate the role for non-sensory derived Ntn1 during cochlear development. These studies will allow us to explore the novel hypothesis that the non-sensory cochlea serves as a source for signaling molecules and will establish the resources needed to study and manipulate non-sensory cells and define their specific contribution to cochlear development, function, and the etiology of deafness.