Early Deletion of Neurod1 Alters Neuronal Lineage Potential and Diminishes Neurogenesis in the Inner Ear.

Iva Filova,Gabriela Pavlinkova,Ebenezer N Yamoah,Romana Bohuslavova,Bernd Fritzsch,Mitra Tavakoli

doi:10.3389/fcell.2022.845461

Abstract

Neuronal development in the inner ear is initiated by expression of the proneural basic Helix-Loop-Helix (bHLH) transcription factor Neurogenin1 that specifies neuronal precursors in the otocyst. The initial specification of the neuroblasts within the otic epithelium is followed by the expression of an additional bHLH factor, Neurod1. Although NEUROD1 is essential for inner ear neuronal development, the different aspects of the temporal and spatial requirements of NEUROD1 for the inner ear and, mainly, for auditory neuron development are not fully understood. In this study, using Foxg1Cre for the early elimination of Neurod1 in the mouse otocyst, we showed that Neurod1 deletion results in a massive reduction of differentiating neurons in the otic ganglion at E10.5, and in the diminished vestibular and rudimental spiral ganglia at E13.5. Attenuated neuronal development was associated with reduced and disorganized sensory epithelia, formation of ectopic hair cells, and the shortened cochlea in the inner ear. Central projections of inner ear neurons with conditional Neurod1 deletion are reduced, unsegregated, disorganized, and interconnecting the vestibular and auditory systems. In line with decreased afferent input from auditory neurons, the volume of cochlear nuclei was reduced by 60% in Neurod1 mutant mice. Finally, our data demonstrate that early elimination of Neurod1 affects the neuronal lineage potential and alters the generation of inner ear neurons and cochlear afferents with a profound effect on the first auditory nuclei, the cochlear nuclei.

Highlights

The inner ear is a highly organized structure of interlinked channels and chambers built to encode sound, space orientation, and motion (Goodrich, 2016; Elliott et al, 2021)
We confirmed Foxg1Cre expression in sensory cells and neurons in the inner ear using tdTomatoAi14 reporter mice (Supplementary Figures S1A,B)
Neurod1CKO failed to thrive from birth to weaning with significant deficits in body size and body weight compared to controls at postnatal day P21

Summary

Introduction

The inner ear is a highly organized structure of interlinked channels and chambers built to encode sound, space orientation, and motion (Goodrich, 2016; Elliott et al, 2021). The sensory organs are represented by five vestibular epithelia (the maculae of utricle and saccule, and the cristae of the three semicircular canal ampullae), and, in mammals, by the auditory sensory organ of the cochlea, the organ of Corti (Rubel and Fritzsch, 2002; Fritzsch et al, 2013). The sensory epithelia are innervated by neurons of the inner ear of two different ganglia, the vestibular and spiral ganglia. The auditory spiral ganglion twists along the length of the cochlear duct with peripheral neuronal processes innervating hair cells within the auditory sensory epithelium and central axons merging into the cochlear nerve (Pavlinkova, 2020). These inner ear neurons transmit received information from the sensory cells to the central nervous system

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