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.

• Keywords
• auditory behavior, auditory maps, auditory nuclei, inferior colliculus, spiral ganglion neurons,
• MeSH
• Spiral Ganglion * enzymology   MeSH
• Cochlea embryology   innervation   MeSH
• Mice MeSH
• Neurogenesis * genetics   MeSH
• Cochlear Nucleus * embryology   MeSH
• LIM-Homeodomain Proteins * genetics   physiology   MeSH
• Auditory Pathways * embryology   MeSH
• Transcription Factors * genetics   physiology   MeSH
• Hair Cells, Auditory * physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• insulin gene enhancer binding protein Isl-1 MeSH Browser
• LIM-Homeodomain Proteins * MeSH
• Transcription Factors * 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.

• Keywords
• auditory system, inferior colliculus, inhibition, sound processing, transcription factor ISL1,
• MeSH
• Inferior Colliculi metabolism   physiology   MeSH
• Gene Expression genetics   MeSH
• Humans MeSH
• Brain physiology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neurons physiology   MeSH
• Promoter Regions, Genetic genetics   MeSH
• LIM-Homeodomain Proteins genetics   metabolism   MeSH
• Hearing MeSH
• Auditory Perception genetics   physiology   MeSH
• Evoked Potentials, Auditory, Brain Stem physiology   MeSH
• Auditory Threshold physiology   MeSH
• PAX2 Transcription Factor genetics   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• insulin gene enhancer binding protein Isl-1 MeSH Browser
• PAX2 protein, human MeSH Browser
• Pax2 protein, mouse MeSH Browser
• LIM-Homeodomain Proteins MeSH
• PAX2 Transcription Factor MeSH
• Transcription Factors 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.

• Keywords
• auditory pathways, cochlea, genetic mutations, single-cell RNAseq, transcription factor,
• MeSH
• Spiral Ganglion embryology   physiology   MeSH
• Induced Pluripotent Stem Cells cytology   MeSH
• Cochlea embryology   physiology   MeSH
• Humans MeSH
• Brain Stem MeSH
• Mutation MeSH
• Mice MeSH
• Neurogenesis MeSH
• Neurons physiology   MeSH
• Cochlear Nucleus embryology   physiology   MeSH
• Hearing Loss, Sensorineural physiopathology   MeSH
• Regenerative Medicine methods   MeSH
• Base Sequence MeSH
• Evoked Potentials, Auditory, Brain Stem MeSH
• Hair Cells, Auditory physiology   MeSH
• Ear, Inner embryology   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

SOX2 is essential for maintaining neurosensory stem cell properties, although its involvement in the early neurosensory development of cranial placodes remains unclear. To address this, we used Foxg1-Cre to conditionally delete Sox2 during eye, ear, and olfactory placode development. Foxg1-Cre mediated early deletion of Sox2 eradicates all olfactory placode development, and disrupts retinal development and invagination of the lens placode. In contrast to the lens and olfactory placodes, the ear placode invaginates and delaminates NEUROD1 positive neurons. Furthermore, we show that SOX2 is not necessary for early ear neurogenesis, since the early inner ear ganglion is formed with near normal central projections to the hindbrain and peripheral projections to the undifferentiated sensory epithelia of E11.5-12.5 ears. However, later stages of ear neurosensory development, in particular, the late forming auditory system, critically depend on the presence of SOX2. Our data establish distinct differences for SOX2 requirements among placodal sensory organs with similarities between olfactory and lens but not ear placode development, consistent with the unique neurosensory development and molecular properties of the ear.

• Keywords
• Eye, Inner ear, Neuronal projections, Olfactory system, Placode development,
• MeSH
• Apoptosis MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neurogenesis * MeSH
• Nasal Mucosa embryology   metabolism   MeSH
• Lens, Crystalline embryology   metabolism   MeSH
• SOXB1 Transcription Factors genetics   metabolism   MeSH
• Ear, Inner cytology   embryology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Sox2 protein, mouse MeSH Browser
• SOXB1 Transcription Factors 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.

• Keywords
• Neurod1 mutation, auditory pathway, cochlear nucleus, inferior colliculus, plasticity, sensory topographical map,
• MeSH
• Behavior, Animal physiology   MeSH
• Inferior Colliculi anatomy & histology   physiology   MeSH
• Spiral Ganglion cytology   physiology   MeSH
• Brain Mapping MeSH
• Mesencephalon embryology   physiology   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Cochlear Nucleus anatomy & histology   physiology   MeSH
• Hearing physiology   MeSH
• Auditory Perception genetics   physiology   MeSH
• Pregnancy MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   physiology   MeSH
• Reflex, Startle genetics   physiology   MeSH
• Vestibule, Labyrinth anatomy & histology   physiology   MeSH
• Pitch Perception physiology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Neurod1 protein, mouse MeSH Browser
• Basic Helix-Loop-Helix Transcription Factors MeSH

The programming of cell fate by transcription factors requires precise regulation of their time and level of expression. The LIM-homeodomain transcription factor Islet1 (Isl1) is involved in cell-fate specification of motor neurons, and it may play a similar role in the inner ear. In order to study its role in the regulation of vestibulo-motor development, we investigated a transgenic mouse expressing Isl1 under the Pax2 promoter control (Tg +/- ). The transgenic mice show altered level, time, and place of expression of Isl1 but are viable. However, Tg +/- mice exhibit hyperactivity, including circling behavior, and progressive age-related decline in hearing, which has been reported previously. Here, we describe the molecular and morphological changes in the cerebellum and vestibular system that may cause the hyperactivity of Tg +/- mice. The transgene altered the formation of folia in the cerebellum, the distribution of calretinin labeled unipolar brush cells, and reduced the size of the cerebellum, inferior colliculus, and saccule. Age-related progressive reduction of calbindin expression was detected in Purkinje cells in the transgenic cerebella. The hyperactivity of Tg +/- mice is reduced upon the administration of picrotoxin, a non-competitive channel blocker for the γ-aminobutyric acid (GABA) receptor chloride channels. This suggests that the overexpression of Isl1 significantly affects the functions of GABAergic neurons. We demonstrate that the overexpression of Isl1 affects the development and function of the cerebello-vestibular system, resulting in hyperactivity.

• Keywords
• Age-related deterioration of Purkinje cells, Attention deficit hyperactivity disorder, Calcium homeostasis, Cerebellum, Foliation defects, GABA signaling, Hyperactivity, Islet1 transcription factor, Purkinje cells, Transgenic mouse, Vestibular system,
• MeSH
• Hyperkinesis metabolism   pathology   MeSH
• Cerebellum metabolism   pathology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• LIM-Homeodomain Proteins biosynthesis   MeSH
• PAX2 Transcription Factor biosynthesis   MeSH
• Transcription Factors biosynthesis   MeSH
• Vestibule, Labyrinth metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• insulin gene enhancer binding protein Isl-1 MeSH Browser
• Pax2 protein, mouse MeSH Browser
• LIM-Homeodomain Proteins MeSH
• PAX2 Transcription Factor MeSH
• Transcription Factors MeSH

The role of Sox2 in neurosensory development is not yet fully understood. Using mice with conditional Islet1-cre mediated deletion of Sox2, we explored the function of Sox2 in neurosensory development in a model with limited cell type diversification, the inner ear. In Sox2 conditional mutants, neurons initially appear to form normally, whereas late- differentiating neurons of the cochlear apex never form. Variable numbers of hair cells differentiate in the utricle, saccule, and cochlear base but sensory epithelium formation is completely absent in the apex and all three cristae of the semicircular canal ampullae. Hair cells differentiate only in sensory epithelia known or proposed to have a lineage relationship of neurons and hair cells. All initially formed neurons lacking hair cell targets die by apoptosis days after they project toward non-existing epithelia. Therefore, late neuronal development depends directly on Sox2 for differentiation and on the survival of hair cells, possibly derived from common neurosensory precursors.

• MeSH
• Gene Deletion MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neurogenesis physiology   MeSH
• Saccule and Utricle cytology   embryology   MeSH
• SOXB1 Transcription Factors genetics   metabolism   MeSH
• Hair Cells, Auditory cytology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Sox2 protein, mouse MeSH Browser
• SOXB1 Transcription Factors MeSH