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

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.

ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization

“…Notably, the functional and spatial organization of SGNs may differ in transcription factor networks required for their differentiation programs. For example, some Neurod1 -lacking neurons survive, form a rudimental cochlear ganglion, and establish bipolar connections to their targets in Neurod1 -null mice ( 12 ) or the otocyst-deleted Neurod1 conditional mutant ( 18 ). Consistent with these findings, neurons forming a segment of the spiral ganglion in the Rosenthal’s canal of Isl1CKO may not require ISL1 for their differentiation and the migration mode.…”

“…Several transcription factors govern the development of inner ear neurons, including NEUROG1 ( 11 ), NEUROD1 ( 12 ), GATA3 ( 13 , 14 ), and POU4F1 ( 15 ). The transcription factor NEUROD1 is vital for the differentiation and survival of inner ear neurons ( 16 – 18 ). We previously demonstrated that Isl1 Cre -mediated Neurod1 deletion ( Neurod1CKO ) results in a disorganized cochleotopic projection from SGNs ( 19 ), affecting acoustic information processing in the central auditory system of adult mice at the physiological and behavioral levels ( 20 ).…”

ISL1 is necessary for auditory neuron development and contributes towards tonotopic organization

“…Notably, the functional and spatial organization of SGNs may differ in transcription factor networks required for their differentiation programs. For example, some Neurod1 lacking neurons survive, form a rudimental cochlear ganglion, and establish bipolar connections to their targets in Neurod1 null mice 11 or the otocyst-deleted Neurod1 conditional mutant 17 . Consistent with these findings, neurons forming a segment of the spiral ganglion in the Rosenthal’s canal of Isl1CKO may not require ISL1 for their differentiation and/or the migration mode.…”

“…Several transcription factors govern the development of inner ear neurons, including NEUROG1 10 , NEUROD1 11 , GATA3 12, 13 , and POU4F1 14 . The transcription factor NEUROD1 is vital for the differentiation and survival of inner ear neurons 15, 16, 17 . We previously demonstrated that Isl1 Cre -mediated Neurod1 deletion ( Neurod1CKO ) results in a disorganized cochleotopic projection from SGNs 18 , affecting acoustic information processing in the central auditory system of adult mice at the physiological and behavioral levels 19 .…”

Application of Human Stem Cells to Model Genetic Sensorineural Hearing Loss and Meniere Disease

“…Development of the inner ear is an organized molecular transformation of a set of epidermal cells (the otic placode) into the fully developed ear with its neurosensory component, necessary for signal extraction and transmission, and the non-sensory component, forming the labyrinth necessary for directing sensory stimuli to specific sensory epithelia [6,94]. The main genes involved in neurosensory development in the inner ear are MYO7A, HES5, SOX2, NEUROG1, NEUROD1, and POU4F1 [80,[95][96][97][98].…”