Development of Cochlear Innervation

Project Summary The mammalian cochlea contains two types of specialized mechanosensors, inner and outer hair cells (IHCs and OHCs), surrounded by distinct inner and outer supporting cell types and differentially innervated by afferent and efferent neurons. The resulting structure and neuronal circuitry are critical for hearing. Our eventual goal is to elucidate how this neural circuit assembles during development, and our overall approach is to alter the identity of some of the cell types involved. In this proposal, by removing or adding the master regulator TBX2 at various times in development we will generate mice with no IHCs and mice in which IHCs convert into ic-OHCs (inner compartment outer hair cells, in the position of the IHCs but with most of the features of OHCs and not of IHCs) at the time of our choosing, either permanently or reversibly. With these manipulations we will be able to address many unanswered questions regarding how auditory neural circuits assemble, such as which cells direct type I afferents to IHCs and their vicinity, what normally limits type II afferents to innervate only OHCs, what is the role of afferents in dictating how and where efferents terminate, and what is the role of IHCs, their contact with type I afferents, and their synaptic communication with them in the formation and maturation of the distinct subtypes of cochlear afferents. Finally, we hope to elucidate whether the contact and formation of functional synapses between IHCs and type I afferent neurons of the cochlear spiral ganglion is restricted to critical developmental periods or may occur later in life.