A Gata3–Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing

  • Yu W
  • Appler J
  • Kim Y
  • et al.
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Abstract

Information flow through neural circuits is determined by the nature of the synapses linking the subtypes of neurons. How neurons acquire features distinct to each synapse remains unknown. We show that the transcription factor Mafb drives the formation of auditory ribbon synapses, which are specialized for rapid transmission from hair cells to spiral ganglion neurons (SGNs). Mafb acts in SGNs to drive differentiation of the large postsynaptic density (PSD) characteristic of the ribbon synapse. In Mafb mutant mice, SGNs fail to develop normal PSDs, leading to reduced synapse number and impaired auditory responses. Conversely, increased Mafb accelerates synaptogenesis. Moreover, Mafb is responsible for executing one branch of the SGN differentiation program orchestrated by the Gata3 transcriptional network. Remarkably, restoration of Mafb rescues the synapse defect in Gata3 mutants. Hence, Mafb is a powerful regulator of cell-type specific features of auditory synaptogenesis that offers a new entry point for treating hearing loss.Different types of neurons in the nervous system communicate with each other through different types of synapses. In the auditory system, for example, it is essential for the timing of signals to be preserved as they are sent from the ear to the brain, and this places special demands on the synapses in this part of the nervous system. In particular, the ribbon synapses that are found between the inner hair cells of the ear, which convert sound waves into neural signals, and the neurons of the spiral ganglion in the cochlea, which carry information about the frequency, intensity and timing of sounds to the brain, can transmit signals with remarkable fidelity.Little is known about the mechanisms by which synapses become specialized for particular functions. Previous work has suggested that a protein called Gata3 is important for the development of the neurons and synapses in the spiral ganglion, including ribbon synapses. Gata3 is a transcription factor that controls the expression of a wide range of genes that are involved in the auditory systems, including genes that are expressed as other transcription factors.Yu et al. used transgenic mice to explore what happened when one of these transcription factors, Mafb, was missing from neurons in the spiral ganglion. The results showed that ribbon synapses did not form when Mafb was absent, which meant that they were unable to respond normally to sounds. Yu et al. also studied mice in which Gata3 was absent: normally Mafb would not be present in these mice, but when genetic techniques were used to force the expression of the gene for Mafb, ribbon synapses were formed. As well as revealing a molecular pathway by which synapses become specialized for rapid and accurate transmission of auditory information, these findings might lead to new approaches to treating hearing loss in humans.

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Yu, W.-M., Appler, J. M., Kim, Y.-H., Nishitani, A. M., Holt, J. R., & Goodrich, L. V. (2013). A Gata3–Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing. ELife, 2. https://doi.org/10.7554/elife.01341

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