A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

• Klíčová slova
• auditory behavior, auditory maps, auditory nuclei, inferior colliculus, spiral ganglion neurons,
• MeSH
• ganglion spirale * enzymologie   MeSH
• kochlea embryologie   inervace   MeSH
• myši MeSH
• neurogeneze * genetika   MeSH
• nucleus cochlearis * embryologie   MeSH
• proteiny s homeodoménou LIM * genetika   fyziologie   MeSH
• sluchová dráha * embryologie   MeSH
• transkripční faktory * genetika   fyziologie   MeSH
• vláskové buňky * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• proteiny s homeodoménou LIM * MeSH
• transkripční faktory * MeSH

The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

• Klíčová slova
• auditory system, inferior colliculus, inhibition, sound processing, transcription factor ISL1,
• MeSH
• colliculus inferior metabolismus   fyziologie   MeSH
• exprese genu genetika   MeSH
• lidé MeSH
• mozek fyziologie   MeSH
• myši transgenní MeSH
• myši MeSH
• neurony fyziologie   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• proteiny s homeodoménou LIM genetika   metabolismus   MeSH
• sluch MeSH
• sluchová percepce genetika   fyziologie   MeSH
• sluchové kmenové evokované potenciály fyziologie   MeSH
• sluchový práh fyziologie   MeSH
• transkripční faktor PAX2 genetika   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• PAX2 protein, human MeSH Prohlížeč
• Pax2 protein, mouse MeSH Prohlížeč
• proteiny s homeodoménou LIM MeSH
• transkripční faktor PAX2 MeSH
• transkripční faktory MeSH

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.

• Klíčová slova
• auditory pathways, cochlea, genetic mutations, single-cell RNAseq, transcription factor,
• MeSH
• ganglion spirale embryologie   fyziologie   MeSH
• indukované pluripotentní kmenové buňky cytologie   MeSH
• kochlea embryologie   fyziologie   MeSH
• lidé MeSH
• mozkový kmen MeSH
• mutace MeSH
• myši MeSH
• neurogeneze MeSH
• neurony fyziologie   MeSH
• nucleus cochlearis embryologie   fyziologie   MeSH
• percepční nedoslýchavost patofyziologie   MeSH
• regenerativní lékařství metody   MeSH
• sekvence nukleotidů MeSH
• sluchové kmenové evokované potenciály MeSH
• vláskové buňky fyziologie   MeSH
• vnitřní ucho embryologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Ear development requires the transcription factors ATOH1 for hair cell differentiation and NEUROD1 for sensory neuron development. In addition, NEUROD1 negatively regulates Atoh1 gene expression. As we previously showed that deletion of the Neurod1 gene in the cochlea results in axon guidance defects and excessive peripheral innervation of the sensory epithelium, we hypothesized that some of the innervation defects may be a result of abnormalities in NEUROD1 and ATOH1 interactions. To characterize the interdependency of ATOH1 and NEUROD1 in inner ear development, we generated a new Atoh1/Neurod1 double null conditional deletion mutant. Through careful comparison of the effects of single Atoh1 or Neurod1 gene deletion with combined double Atoh1 and Neurod1 deletion, we demonstrate that NEUROD1-ATOH1 interactions are not important for the Neurod1 null innervation phenotype. We report that neurons lacking Neurod1 can innervate the flat epithelium without any sensory hair cells or supporting cells left after Atoh1 deletion, indicating that neurons with Neurod1 deletion do not require the presence of hair cells for axon growth. Moreover, transcriptome analysis identified genes encoding axon guidance and neurite growth molecules that are dysregulated in the Neurod1 deletion mutant. Taken together, we demonstrate that much of the projections of NEUROD1-deprived inner ear sensory neurons are regulated cell-autonomously.

• Klíčová slova
• Axon guidance, Central projections, Ear neurosensory development, Neuronal differentiation, bHLH genes,
• MeSH
• apoptóza genetika   MeSH
• axony metabolismus   MeSH
• biologické modely MeSH
• buněčná diferenciace genetika   MeSH
• Cortiho orgán patologie   MeSH
• delece genu MeSH
• epitel metabolismus   MeSH
• ganglion spirale metabolismus   MeSH
• mutace genetika   MeSH
• myši knockoutované MeSH
• nervová vlákna metabolismus   MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• stanovení celkové genové exprese MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• transkripční faktory SOXB1 metabolismus   MeSH
• vláskové buňky metabolismus   patologie   ultrastruktura   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Atoh1 protein, mouse MeSH Prohlížeč
• Neurogenic differentiation factor 1 MeSH Prohlížeč
• proteiny nervové tkáně MeSH
• transkripční faktory bHLH MeSH
• transkripční faktory SOXB1 MeSH

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

• Klíčová slova
• Neurod1 mutation, auditory pathway, cochlear nucleus, inferior colliculus, plasticity, sensory topographical map,
• MeSH
• chování zvířat fyziologie   MeSH
• colliculus inferior anatomie a histologie   fyziologie   MeSH
• ganglion spirale cytologie   fyziologie   MeSH
• mapování mozku MeSH
• mezencefalon embryologie   fyziologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• nucleus cochlearis anatomie a histologie   fyziologie   MeSH
• sluch fyziologie   MeSH
• sluchová percepce genetika   fyziologie   MeSH
• těhotenství MeSH
• transkripční faktory bHLH genetika   fyziologie   MeSH
• úleková reakce genetika   fyziologie   MeSH
• vestibulární aparát anatomie a histologie   fyziologie   MeSH
• vnímání výšky zvuku fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Neurod1 protein, mouse MeSH Prohlížeč
• transkripční faktory bHLH MeSH