Correction: Neurogenesis in the inner ear: the zebrafish statoacoustic ganglion provides new neurons from a Neurod/Nestin-positive progenitor pool well into adulthood

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.

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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

Filova

Bohuslavová

Tavakoli

et al. 2022

“…We recently showed the presence of a lifelong but almost quiescent neurogenic niche in the adult zebrafish statoacoustic ganglion (SAG). It comprises a pool of Neurod-positive neuronal progenitor cells, which are replenished by marker-negative presumptive stem cells ( Schwarzer et al, 2020 ). To investigate whether sensory neurons of the adult SAG can regenerate and whether the neurogenic niche is the source of these newly generated sensory neurons, we aimed to establish the first lesion paradigm of the zebrafish SAG.…”

Section: Resultsmentioning

confidence: 99%

“…During homeostasis, neurogenesis in the zebrafish SAG decreases significantly to very low levels at adult stages (Schwarzer et al, 2020).…”

Section: Reactive Proliferation In the Neurogenic Niche Of The Adult ...mentioning

confidence: 99%

“…In sharp contrast, knowledge on the formation of inner ear neurons during regeneration in the regeneration-competent zebrafish is currently completely lacking. We recently showed the lifelong existence of a neurogenic niche in the eighth cranial nerve, also known as statoacoustic ganglion (SAG), in zebrafish ( Schwarzer et al, 2020 ). We found that Neurod-positive progenitors proliferate and produce large amounts of new neurons at juvenile stages, but transition to a quiescent state at adulthood with only very rare neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reactivation of the Neurogenic Niche in the Adult Zebrafish Statoacoustic Ganglion Following a Mechanical Lesion

Schwarzer

Rekhade

Machate

et al. 2022

Self Cite

Sensorineural hearing loss is caused by the loss of sensory hair cells and/or their innervating neurons within the inner ear and affects millions of people worldwide. In mammals, including humans, the underlying cell types are only produced during fetal stages making loss of these cells and the resulting consequences irreversible. In contrast, zebrafish produce sensory hair cells throughout life and additionally possess the remarkable capacity to regenerate them upon lesion. Recently, we showed that also inner ear neurogenesis continues to take place in the zebrafish statoacoustic ganglion (SAG) well into adulthood. The neurogenic niche displays presumptive stem cells, proliferating Neurod-positive progenitors and a high level of neurogenesis at juvenile stages. It turns dormant at adult stages with only a few proliferating presumptive stem cells, no proliferating Neurod-positive progenitors, and very low levels of newborn neurons. Whether the neurogenic niche can be reactivated and whether SAG neurons can regenerate upon damage is unknown. To study the regenerative capacity of the SAG, we established a lesion paradigm using injections into the otic capsule of the right ear. Upon lesion, the number of apoptotic cells increased, and immune cells infiltrated the SAG of the lesioned side. Importantly, the Neurod-positive progenitor cells re-entered the cell cycle displaying a peak in proliferation at 8 days post lesion before they returned to homeostatic levels at 57 days post lesion. In parallel to reactive proliferation, we observed increased neurogenesis from the Neurod-positive progenitor pool. Reactive neurogenesis started at around 4 days post lesion peaking at 8 days post lesion before the neurogenesis rate decreased again to low homeostatic levels at 57 days post lesion. Additionally, administration of the thymidine analog BrdU and, thereby, labeling proliferating cells and their progeny revealed the generation of new sensory neurons within 19 days post lesion. Taken together, we show that the neurogenic niche of the adult zebrafish SAG can indeed be reactivated to re-enter the cell cycle and to increase neurogenesis upon lesion. Studying the underlying genes and pathways in zebrafish will allow comparative studies with mammalian species and might provide valuable insights into developing cures for auditory and vestibular neuropathies.

Vestibular physiology and function in zebrafish

Baeza-Loya

Raible

2023

The vestibular system of the inner ear provides information about head motion and spatial orientation relative to gravity to ensure gaze stability, balance, and postural control. Zebrafish, like humans, have five sensory patches per ear that serve as peripheral vestibular organs, with the addition of the lagena and macula neglecta. The zebrafish inner ear can be easily studied due to its accessible location, the transparent tissue of larval fish, and the early development of vestibular behaviors. Thus, zebrafish are an excellent model for studying the development, physiology, and function of the vestibular system. Recent work has made great strides to elucidate vestibular neural circuitry in fish, tracing sensory transmission from receptors in the periphery to central computational circuits driving vestibular reflexes. Here we highlight recent work that illuminates the functional organization of vestibular sensory epithelia, innervating first-order afferent neurons, and second-order neuronal targets in the hindbrain. Using a combination of genetic, anatomical, electrophysiological, and optical techniques, these studies have probed the roles of vestibular sensory signals in fish gaze, postural, and swimming behaviors. We discuss remaining questions in vestibular development and organization that are tractable in the zebrafish model.