Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain

Abstract

Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.

Keywords: auditory cortex; cochlea; cochlear nucleus; inferior colliculus; medial geniculate body; superior olivary complex.

Figure 1

Molecular factors guide the development and organization of the sensory HCs. (a) The expression of Eya1/Six1/Brg1 and Sox2 in prosensory progenitors is followed by Atoh1, which is needed for hair cell development. The downstream transcription factors Pou4f3 and Gfi1 are required to maintain hair cells. Tbx1/2/3 interact with Neurog1, Foxg1, and Fgf10 to regulate neural fate and inner ear morphogenesis. Deletion of these factors results in a reduced number and distribution of SGNs and a shorter cochlea with an increased number of HCs. HCs are lost in mice in the absence of Pax2, Gata3, and Lmx1a/b. Tbx2, Srrm3/4, and Fgf8 are needed for the differentiation and viability of IHCs. Insm1, Ikzf2, and Fgf20 are necessary for the differentiation of OHCs and/or to form three rows of OHCs. Panel a represents concepts and data from Chizhikov et al. (2021), Elliott et al. (2018), Filova et al. (2022b), García-Añoveros et al. (2022), Kaiser et al. (2021), Nakano et al. (2020), and Xu et al. (2021). (b–d) The isolated auditory sensory epithelium organ of Corti is immunolabeled with anti-neurofilament (green) to label fibers from the SGNs and with anti-Myo7a (red) to label HCs. Panels b–d adapted with permission from Jahan et al. (2018). (b) IHCs and OHCs are organized into one and three parallel rows, respectively, contacted by afferent SGNs. (c) The absence of Srrm4 results in near complete loss of IHCs, with fibers aberrantly targeting the OHCs. (d) Delayed expression of Atoh1 results in one row of IHCs and one row of OHCs that nevertheless remain innervated. Abbreviations: HC, hair cell; IHC, inner hair cell; OHC, outer hair cell; P, postnatal day; SGN, spiral ganglion neuron.

Figure 2

Molecular factors guide the development and organization of the SGNs and their connections. (a) Progenitors and precursors depend on the initial expression of Eya1/Six1/Brg1, Sox2, and Neurog1, which activate several genes required for the differentiation of the SGNs. A large set of genes are necessary downstream, but the transcriptional factors Neurod1, Isl1, and Pou4f1 are crucial, as well as Pax2, Gata3, and Lmx1a/b. SGNs further differentiate into four populations: type Ia, Ib, Ic, and II. Unique patterns of gene expression are required for the differentiation and identification of these neuronal subtypes. Panel a represents concepts and data from Bouchard et al. (2010), Chizhikov et al. (2021), Dvorakova et al. (2020), Elliott et al. (2021a,c), Filova et al. (2022b), Ma et al. (2000), Petitpré et al. (2022), Sun & Liu (2023), and Xu et al. (2021). (b,c) The isolated organ of Corti is shown, where fibers from the SGNs have been traced with lipophilic dyes (panel b, green) or identified via transgenic expression of peripherin-eGFP (panel c, green). Hair cells are identified by immunolabeling with anti-Myo7a (purple, panel b only). (b) By P2, fibers from the SGNs begin to contact the IHCs. Panel b adapted from Fritzsch (2023). (c) By P4, both IHCs and OHCs are contacted by fibers from the SGNs. Panel c adapted from Elliott et al. (2021a) (CC BY 4.0). Abbreviations: eGFP, enhanced green fluorescent protein; IHC, inner hair cell; OHC, outer hair cell; P, postnatal day; SGN, spiral ganglion neuron.

Figure 3

Molecular factors guide the development of projections to the CN and their tonotopic organization. (a) Progenitors depend on Lmx1a/b, Wnt1/3a, and Sox2 to express Atoh1 and then Neurod1 before they differentiate to develop into excitatory glutamatergic neurons. In addition, Ptf1a expression guides the development of inhibitory glycinergic and GABAergic neurons. Panel a represents concepts and data from Chizhikov et al. (2021), Elliott et al. (2021c, 2023), Filova et al. (2022a), and Wang et al. (2005). (b) Projection pathways from the inner ear into the CN, including the AVCN, PVCN, and DCN, as well as the VG, are identified using lipophilic dyes. Projections from the cochlear base are labeled by red dye, whereas apical projections are labeled by green dye. The most ventral projections into the CN arise (green) from the apical region of the cochlea, while the dorsal projections (red) arise from the basal region of the cochlea. (c) Deletion of Neurod1 driven by Foxg1-cre results in central projections that fail to segregate tonotopically. Panel c adapted with permission from Filova et al. (2022a). Abbreviations: AVCN, anteroventral cochlear nucleus; CN, cochlear nucleus; DCN, dorsal cochlear nucleus; E, embryonic day; P, postnatal day; PVCN, posteroventral cochlear nucleus; r, rhombomere; VG, vestibular ganglion.

Figure 4

Molecular factors guide the development of neurons in the IC and AC and establish the projection pathways from the brainstem to the AC. (a) Progenitors in the AC depend on Pax6/Tbr1/2 and Foxg1 to induce Sox2 to in turn induce neurons that depend on Neurod1 and Neurog2 to differentiate into excitatory glutamatergic neurons. Progenitors in the IC depend on Lmx1a/b/Gdf7, Wnt1, and Sox2 to induce neurons that also then depend on Neurod1 and Neurog2 to differentiate into excitatory glutamatergic neurons. Panel a represents concepts and data from Glover et al. (2018) and Hevner (2022). (b) Outputs of the four major types of neurons in the CN project to the SOC, which comprises four main nuclei: the LSO, MSO, MNTB, and LNTB. The LSO receives a binaural input originating from the ipsilateral Sbcs and contralateral Gbcs, the latter of which are inhibited by neurons from the MNTB. The MSO receives bilateral excitatory input from the Sbcs and bilateral inhibitory input from the Gbcs via the MNTB and the LNTB. The Octs provide bilateral input to the SPON and eventually connect with the LL. Not shown are the T-stellate cells, which terminate in distinct regions of the SOC, LL, and IC. The output from the dorsal CN, from Fus neurons, bypasses the SOC to reach the contralateral IC. Additionally, the MGB receives input from the IC and projects to the AC. These interactions play significant roles in processing auditory information along the neural pathway. The molecular factors guiding the development of these projection pathways are poorly understood. Panel b represents concepts and data from Kandler et al. (2020), Malmierca (2015), Molnár et al. (2020), Pecka & Encke (2020), Rees (2020), and Tran et al. (2023). Abbreviations: AC, auditory cortex; CN, cochlear nucleus; Fus, fusiform; Gbc, globular bushy cell; IC, inferior colliculus; L, layer; LL, lateral lemniscus; LNTB, lateral nucleus of the trapezoid body; LSO, lateral superior olive; MGB, medial geniculate body; MNTB, medial nucleus of the trapezoid body; MSO, medial superior olive; Oct, octopus cell; Sbc, spherical bushy cell; SOC, superior olivary complex; SPON, superior paraolivary nucleus.