Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers

Filova, Iva; Dvorakova, Martina; Bohuslavová, Romana; Pavlinek, Adam; Elliott, Karen L.; Vochyánová, Simona; Fritzsch, Bernd; Pavlínková, Gabriela

doi:10.1007/s12035-020-02092-0

Cited by 21 publications

(64 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Loss of Neurod1 resulted in a prolonged Atoh1 expression in sensory neurons and differentiation of some of these Atoh1-positive cells into ectopic "intraganglionic" HCs [28]. Furthermore, Neurod1 elimination in differentiating SGNs resulted in the formation of an abnormal spiral-vestibular ganglion [42,43], including the formation of vesicles containing several Atoh1-positive "HCs" [28,44]. These neurons overlap with the transient Atoh1-positive cells, suggesting Atoh1 is typically suppressed by Neurod1, consistent with the regulation of Atoh1 in the cerebellum [38] and the intestine [45].…”

Section: Neurog1 Regulates Neurod1 and Atoh1 Expression And Is Essentmentioning

confidence: 99%

Development in the Mammalian Auditory System Depends on Transcription Factors

Elliott

Pavlínková

Chizhikov

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Neurog1 Regulates Neurod1 and Atoh1 Expression And Is Essentmentioning

confidence: 99%

Development in the Mammalian Auditory System Depends on Transcription Factors

Elliott

Pavlínková

Chizhikov

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, the absence of Neurod1 affects the tonotopic organization of the cochlea, resulting in a disorganized primary tonotopic map and altered features of acoustic signal processing in the central auditory system [ 6 ]. Additionally, a novel Neurod1 and Atoh1 double-deletion mutant demonstrates that Neurod1 -deprived auditory neurons form projections without any sensory cells present in the cochlea after the Atoh1 elimination ( Neurod1;Atoh1CKO ; Figure 4 D) [ 52 ]. This study suggests that auditory neurons with Neurod1 deletion are able to grow axons and form neuronal projections cell autonomously [ 52 ].…”

Section: Transcriptional Network In the Development And Maintenancmentioning

confidence: 99%

“…Additionally, a novel Neurod1 and Atoh1 double-deletion mutant demonstrates that Neurod1 -deprived auditory neurons form projections without any sensory cells present in the cochlea after the Atoh1 elimination ( Neurod1;Atoh1CKO ; Figure 4 D) [ 52 ]. This study suggests that auditory neurons with Neurod1 deletion are able to grow axons and form neuronal projections cell autonomously [ 52 ]. Thus, NEUROD1 has a particularly profound role in the regulation of neuronal branching, organization of projecting afferent and efferent fibers, and tonotopic organization of the auditory system.…”

Section: Transcriptional Network In the Development And Maintenancmentioning

confidence: 99%

“…ISL1 contributes to the development of neuronal and non-neuronal cell types, including motor, sensory, and sympathetic neurons [ 57 , 58 ] and pancreatic endocrine [ 59 ] and cardiac cells [ 60 ]. During ear development, ISL1 is expressed in the differentiating neurons in the cochlea-vestibular ganglion and in prosensory precursors in the ear [ 41 , 52 , 61 ]. Models with the transgenic modulation of Isl1 expression indicate the important roles of ISL1 in the maintenance and function of neurons and hair cells in the inner ear and, also, as a possible contributing factor in neurosensory degeneration [ 62 , 63 , 64 ].…”

Section: Transcriptional Network In the Development And Maintenancmentioning

confidence: 99%

“…( A ) Whole-mount immunostaining with anti-Myo7a (a marker of hair cells, HCs) and anti-ß-tubulin (nerve fibers) antibodies shows the innervation and the formation of the sensory epithelium and hair cells in the mouse control cochlea at postnatal day 0. ( B ) Delayed deletion of the SRY (sex-determining region Y)-box 2 ( Sox2 ) [ 41 ], ( C ) Neurod1 [ 6 ], and ( D ) double deletion of Neurod1 and Atoh1 [ 52 ] were generated by Isl1 Cre and result in abnormalities in the number of neurons, formation of sensory epithelium, and cochlear innervation. Scale bars, 50 μm.…”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Molecular Aspects of the Development and Function of Auditory Neurons

Pavlínková

2020

IJMS

Self Cite

View full text Add to dashboard Cite

This review provides an up-to-date source of information on the primary auditory neurons or spiral ganglion neurons in the cochlea. These neurons transmit auditory information in the form of electric signals from sensory hair cells to the first auditory nuclei of the brain stem, the cochlear nuclei. Congenital and acquired neurosensory hearing loss affects millions of people worldwide. An increasing body of evidence suggest that the primary auditory neurons degenerate due to noise exposure and aging more readily than sensory cells, and thus, auditory neurons are a primary target for regenerative therapy. A better understanding of the development and function of these neurons is the ultimate goal for long-term maintenance, regeneration, and stem cell replacement therapy. In this review, we provide an overview of the key molecular factors responsible for the function and neurogenesis of the primary auditory neurons, as well as a brief introduction to stem cell research focused on the replacement and generation of auditory neurons.

show abstract

A human induced pluripotent stem cell-based modular platform to challenge sensorineural hearing loss

2021

Self Cite

View full text Add to dashboard Cite

The sense of hearing depends on a specialized sensory organ in the inner ear, called the cochlea, which contains the auditory hair cells (HCs). Noise trauma, infections, genetic factors, side effects of ototoxic drugs (ie, some antibiotics and chemotherapeutics), or simply aging lead to the loss of HCs and their associated primary neurons. This results in irreversible sensorineural hearing loss (SNHL) as in mammals, including humans; the inner ear lacks the capacity to regenerate HCs and spiral ganglion neurons. SNHL is a major global health problem affecting millions of people worldwide and provides a growing concern in the aging population. To date, treatment options are limited to hearing aids and cochlear implants. A major bottleneck for development of new therapies for SNHL is associated to the lack of human otic cell bioassays. Human induced pluripotent stem cells (hiPSCs) can be induced in two-dimensional and three-dimensional otic cells in vitro models that can generate inner ear progenitors and sensory HCs and could be a promising preclinical platform from which to work toward restoring SNHL. We review the potential applications of hiPSCs in the various biological approaches, including disease modeling, bioengineering, drug testing, and autologous stem cell based-cell therapy, that offer opportunities to understand the pathogenic mechanisms of SNHL and identify novel therapeutic strategies.

show abstract

Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers

Cited by 21 publications

References 49 publications

Development in the Mammalian Auditory System Depends on Transcription Factors

Development in the Mammalian Auditory System Depends on Transcription Factors

Molecular Aspects of the Development and Function of Auditory Neurons

A human induced pluripotent stem cell-based modular platform to challenge sensorineural hearing loss

Contact Info

Product

Resources

About