Neuropilin-2/Semaphorin-3F-mediated repulsion promotes inner hair cell innervation by spiral ganglion neurons

  • Coate T
  • Spita N
  • Zhang K
  • et al.
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Auditory function is dependent on the formation of specific innervation patterns between mechanosensory hair cells (HCs) and afferent spiral ganglion neurons (SGNs). In particular, type I SGNs must precisely connect with inner HCs (IHCs) while avoiding connections with nearby outer HCs (OHCs). The factors that mediate these patterning events are largely unknown. Using sparse-labeling and time-lapse imaging, we visualized for the first time the behaviors of developing SGNs including active retraction of processes from OHCs, suggesting that some type I SGNs contact OHCs before forming synapses with IHCs. In addition, we demonstrate that expression of Semaphorin-3F in the OHC region inhibits type I SGN process extension by activating Neuropilin-2 receptors expressed on SGNs. These results suggest a model in which cochlear innervation patterns by type I SGNs are determined, at least in part, through a Semaphorin-3F-mediated inhibitory signal that impedes processes from extending beyond the IHC region.The process of hearing begins when sound waves enter the outer ear, causing the eardrum to vibrate. The three small bones of the middle ear pass these vibrations on to the cochlea, a fluid-filled structure shaped like a spiral. Tiny hair cells inside the cochlea move in response to the vibrations and convert them into electrical signals, which are transmitted by cells called spiral ganglion neurons (SGNs) to the brain.Hair cells can be divided into ‘inner’ and ‘outer’ hair cells. Inner hair cells transmit most of the information about a sound to the brain, via connections with type I SGNs. Outer hair cells are thought to amplify sound and connect to type II SGNs. How the type I and II SGNs connect to the correct type of hair cell as the ear develops is not well understood, despite these connections being essential for hearing.Coate et al. have now used time-lapse imaging and fixed specimens to follow individually labeled SGNs as they establish these connections within the cochlea of a mouse embryo. Although the type I SGNs ultimately formed connections with inner hair cells, many of them made contact with outer hair cells first. These contacts were short-lived thanks to a protein found near the outer hair cells, named Semaphorin-3F. This protein repels the type I SGNs by activating a receptor on their surface called Neuropilin-2, and so directs the type I SGNs towards the inner hair cells.One of the mysteries that remains to be solved is how type II SGNs are ‘permitted’ to extend into the outer hair cell region, even though they are also confronted by Semaphorin-3F. In addition, it will also be important to determine how SGNs adapt to cues from different Semaphorins from different parts of the cochlea as they navigate into different hair cell regions.




Coate, T. M., Spita, N. A., Zhang, K. D., Isgrig, K. T., & Kelley, M. W. (2015). Neuropilin-2/Semaphorin-3F-mediated repulsion promotes inner hair cell innervation by spiral ganglion neurons. ELife, 4.

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