Development in the Mammalian Auditory System Depends on Transcription Factors

Abstract

We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix–loop–helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons’ fate into “hair cells”, highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of “intraganglionic” HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

Axonal Projection Patterns of the Dorsal Interneuron Populations in the Embryonic Hindbrain

“…A combinatorial expression of the LIM-homeodomain (LIM-HD) transcription factors Lhx2 and Lhx9, the Barh like homeobox transcription factor Barhl1/2, and the POU domain class 4 transcription factor 1 Pou4f1 accompanies dA1 neural differentiation and migration (Figures 1B,C) (Helms and Johnson, 2003;Wang et al, 2005;Kohl et al, 2012;Hernandez-Miranda et al, 2017). Moreover, the two Lim homeobox transcription factors, Lmx1a and Lmx1b, which are expressed in the roof-plate dorsal to dA1 group, are necessary for their specification (Elliott et al, 2021). Extensive fate map studies in mouse and chick hindbrains, together with the generation of knock-in and knock-out mice lines revealed a wealth of derivatives that originate from dA1 INs, depending upon their rhombomeric origin and time of birth; At r1, dA1 neurons give rise to cerebellar granule cells whereas at r2-r8 they give rise to excitatory neurons that assemble various sorts of brainstem nuclei, with some divergence in their rhombomeric origin in avian and mammalians (Farago et al, 2006;Nothwang, 2016;Lipovsek and Wingate, 2018).…”

“…These different neuronal subtypes were found to depend on their rhombomeric origin; in r1, the most dorsal part of the RL contributes a large migratory cell population that forms the external and internal granular layers of the cerebellum (Ben-Arie et al, 1997;Wingate and Hatten, 1999;Köster and Fraser, 2001;Machold and Fishell, 2005). In r2-r6, the same RL domain generates auditory and vestibular nuclei, through which information is processed and relayed to the upper brain and spinal cord, whereas, in r6-r8, it will give rise to multiple pre-cerebellar nuclei which relay peripheral sensation to the cerebellum through mossy fiber neurons Bayer, 1980, 1987a,b,c,d;Rubel and Parks, 1988;Cambronero and Puelles, 2000;Rodriguez and Dymecki, 2000;Bermingham et al, 2001;Díaz et al, 2003;Ryugo and Parks, 2003;Pasqualetti et al, 2007;Hoshino et al, 2013;Kratochwil et al, 2017;Díaz and Puelles, 2019;Elliott et al, 2021). Similarly, different types of respiratory and viscerosensory nuclei are suggested to be born from more ventral positions of the RL at distinct axial levels, such as the parabrachial and Kölliker-Fuse nuclei that derive from r1, the A5 and intertrigeminal region that derives from r4-r6, the PreBötzinger complex and retrotrapezoid nucleus (RTN) that derive from r3/r5, and the nucleus tractus solitaries that is thought to derive from more posterior rhombomeres (Qian et al, 2001;Gray, 2008).…”

Central auditory deficits associated with genetic forms of peripheral deafness

“…In addition to the central auditory deficits described above, which constitute an ensemble of indirect effects potentially common to all forms of congenital peripheral deafness, other indirect central deficits may be present in some specific genetic forms of congenital deafness. For instance, genetic factors and migration guidance and targeting cues control the initial coarse arrangement of the connections of auditory neuronal circuits (Cramer and Gabriele 2014;Elliott et al 2021). The nascent neuronal networks then mature, in a process driven initially by bursts of spontaneous (i.e.…”

Otic Neurogenesis in Xenopus laevis: Proliferation, Differentiation, and the Role of Eya1

“…The otic placode of vertebrates contains a neurosensory domain with neurosensory progenitor pools that give rise to the sensory hair cells of the inner ear responding to vestibular and auditory stimuli as well as to the sensory neurons of the vestibulocochlear ganglion (reviewed in Alsina et al, 2009 ; Wu and Kelley, 2012 ; Maier et al, 2014 ; Alsina, 2020 ; Elliott et al, 2021 ; Schlosser, 2021 ). Because of its central importance for the vertebrate senses of balance and hearing, the generation of sensory hair cells and sensory neurons from the otic vesicle has been described in several vertebrate model organisms, viz.…”

“…The otic placode of vertebrates contains a neurosensory domain with neurosensory progenitor pools that give rise to the sensory hair cells of the inner ear responding to vestibular and auditory stimuli as well as to the sensory neurons of the vestibulocochlear ganglion (reviewed in Alsina et al, 2009;Wu and Kelley, 2012;Maier et al, 2014;Alsina, 2020;Elliott et al, 2021;Schlosser, 2021).…”