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Mammalian hearing requires the development of the organ of Corti, a sensory epithelium comprising unique cell types. The limited number of each of these cell types, combined with their close proximity, has prevented characterization of individual cell types and/or their developmental progression. To examine cochlear development more closely, we transcriptionally profile approximately 30,000 isolated mouse cochlear cells collected at four developmental time points. Here we report on the analysis of those cells including the identification of both known and unknown cell types. Trajectory analysis for OHCs indicates four phases of gene expression while fate mapping of progenitor cells suggests that OHCs and their surrounding supporting cells arise from a distinct (lateral) progenitor pool. Tgfβr1 is identified as being expressed in lateral progenitor cells and a Tgfβr1 antagonist inhibits OHC development. These results provide insights regarding cochlear development and demonstrate the potential value and application of this data set. How the development of the cochlear epithelium is regulated is unclear. Here, the authors use single cell RNAseq analysis to provide insight into the transcriptional changes arising during development of the murine cochlear inner and outer hair cells.

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.

Morphogens cooperate to guide development of the inner ear cochlea, but how do compartments communicate? A recent study in PLOS Biology reveals how planar cell polarity of individual cells is integrated across distinct regional compartments to ensure proper organ morphogenesis.

PurposeA distinct form of cochlear hypoplasia, characterized by the preservation of the first half of the basal turn with hypoplastic and anteriorly displaced upper turns, was historically associated with branchio-oto-renal (BOR) syndrome, but can also occur in other genetic, syndromic and non-syndromic causes of hearing loss. This study aims to describe this phenotype with relative preservation of the basal turn, particularly its first half, in a significant proportion of cochlear hypoplasia cases due to different causes.MethodsWe retrospectively reviewed temporal bone imaging from 125 patients (250 ears) with cochlear malformations from a tertiary pediatric center, focusing on cases where the basal turn was partially or completely preserved. Temporal bone CT and internal auditory meatus MRI were assessed for cochlear morphology and associated anomalies and genetic, clinical and syndromic associations described.ResultsFifty-eight patients exhibited a preserved basal turn with different degrees of hypoplasia of the upper turns. These cases were grouped into five etiological clusters: branchio-oto-renal (BOR), CHARGE, Walker-Warburg (WWS) syndromes, other genetic cases and likely non-genetic cases (including syndromic conditions without a genetic cause identified such as oculo-auriculo-vertebral spectrum - OAVS). Genetic cases may show bilateral and symmetrical appearances, aberrant facial nerve courses were observed in 30 patients.ConclusionsPreservation of the first half of the basal turn suggests developmental arrest between 50 and 54 days of gestation, and is common across genetic and non-genetic conditions of cochlear hypoplasia. Frequent facial nerve anomalies may complicate cochlear implantation. Integrating imaging with embryological insights supports the need for refined, developmentally-based classification systems.

Hair-cell triggers Cochlear hair cells form the sound-sensing apparatus of vertebrates and their loss or damage results in hearing impairment. Mammals cannot regenerate these cells, but previous work has shown that ectopic expression of the transcription factor Atonal homologue 1 (Atoh1) can induce cells that would not normally differentiate as cochlear hair cells to become hair cell-like. Now Gubbels et al . show that i n utero gene transfer of Atoh1 into mouse cochleas generates ectopic hair cells in the cochlea. Importantly, these supernumerary hair cells are functionally competent and display neuronal connectivity. This is a major step towards experiments to test for the ability of gene therapies to ameliorate hearing loss in mouse models of human deafness. Sensory hair cells in the mammalian cochlea convert mechanical stimuli into electrical impulses that subserve audition 1 , 2 . Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment 3 . Atonal homologue 1 (encoded by Atoh1 , also known as Math1 ) is a basic helix–loop–helix transcription factor required for hair-cell development 4 , 5 , 6 , and its misexpression in vitro 7 , 8 and in vivo 9 , 10 generates hair-cell-like cells. Atoh1 -based gene therapy to ameliorate auditory 10 and vestibular 11 dysfunction has been proposed. However, the biophysical properties of putative hair cells induced by Atoh1 misexpression have not been characterized. Here we show that in utero gene transfer of Atoh1 produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes and express the ribbon synapse marker carboxy-terminal binding protein 2 (refs 12 , 13 ). Moreover, the hair cells are capable of mechanoelectrical transduction 1 , 2 and show basolateral conductances with age-appropriate specializations. Our results demonstrate that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. We expect that our in utero gene transfer paradigm will enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness 14 , 15 .

This study investigated the expression of calretinin (CR) in the mouse cochlea from embryonic day 17 (E17) to adulthood through immunofluorescence. At E17, CR immunoreactivity was only detected in the inner hair cells (IHCs). At E19, the IHCs and spiral ganglion neurons (SGNs) begin to express CR. At birth, CR immunoreactivity was confined primarily to the IHCs and the majority of the SGNs, as identified by TUJ1, both the cytoplasm and the nucleus of SGNs exhibited CR positivity. At postnatal day 2 (P2), auditory nerve fibers reaching the IHCs were stained for CR. CR continued to be expressed in the IHCs, whereas only single row of outer hair cells (OHCs) were positive for CR. By P5, CR expression was evident in IHCs and the three rows of OHCs, with SGNs soma and their neurite projections also displaying CR immunoreactivity. From P8 through adulthood, CR expression persisted in the SGNs and their afferent neurite projections to the IHCs, as well as in IHCs and OHCs. Dual labeling of CR with afferent nerve marker neurofilament 200 (NF200) demonstrated that NF 200-positive SGN somas were encompassed by CR-labeled plasma membrane of SGNs, and NF 200 was co-localized with CR in the afferent nerve fibers innervating the IHCs. We also described the expression of peripherin, a marker for type II SGNs, in the mouse cochlea at various postnatal stages. Peripherin showed a distinct spatio-temporal expression compared to CR in auditory nerve fibers. No co-expression of peripherin and CR was detected in adult. Dynamic expression patterns of CR in the embryonic and postnatal cochlea supported its roles in cochlear development.

High potassium concentration in the cochlear endolymph electrically drives hair cell activity. Sodium potassium ATPase (Na + /K + -ATPase) is an essential pump for ion homeostasis in the cochlea. Most of our knowledge regarding Na + /K + -ATPase has been obtained from rodent models, and knowledge of its distribution in primates, including humans, is limited. This study investigated the distribution of Na + /K + -ATPase in a common marmoset primate model. We investigated expression patterns of Na + /K + -ATPase α1 (ATP1A1), Na + /K + -ATPase α2 (ATP1A2), Na + /K + -ATPase α3 (ATP1A3), Na + /K + -ATPase β1 (ATP1B1), Na + /K + -ATPase β2 (ATP1B2), and Na + /K + -ATPase β3 (ATP1B3) in the cochlea of the neonates and the embryos of the common marmoset. We have described the distributions of specific pairs of Na + /K + -ATPase α and β subunits in each cochlear part, including spiral ganglion neurons, stria vascularis, and the organ of Corti. We also described developmental changes in Na + /K + -ATPases in common marmosets. The distribution of Na + /K + -ATPases in the common marmoset is similar to that in humans and is suitable for furthering our understanding of human cochlear development. The distribution established in this report will aid the study of primate-specific ion homeostasis in the inner ear.

In the present study, the expression of S100β was examined in the mouse cochlea from embryonic day 17 (E17) to postnatal day 32 (P32) using immunofluorescence, aiming to explore its possible role in auditory system. At E17, S100β expression was not detected, except in the external cochlear wall. Starting at E18.5, S100β staining appeared in the organ of Corti and the stria vascularis. In the E18.5 and P1 organ of Corti, S100β was confined to the developing pillar cells. By P6, cytoplasmic staining of S100β was evident in the inner and outer pillar cells, forming the tunnel of Corti. Additionally, S100β expression extended medially into the three rows of Deiter’s cells, with labeling of their phalangeal processes. At P8, S100β continued to be expressed in the heads, bodies, and feet of the two pillar cells, as well as in the soma and phalangeal processes of the three rows of Deiter’s cells. In the lateral wall of the P8 cochlea, S100β was expressed not only in the stria vascularis but also in the spiral ligament. Between P10 and P12, S100β expression was maintained in the Deiter’s cells and pillar cells of the organ of Corti, as well as in the lateral wall, and spiral limbus. From P14 onwards, S100β expression ceased in the stria vascularis, though it persisted in the spiral ligament and spiral limbus into adulthood. Within the P14 and P21 organ of Corti, S100β remained in the Deiter’s and pillar cells. S100β immunostaining was not observed in the phalangeal processes of Deiter’s cells but was specifically present in the Deiter’s cell cups at P21. In the adult cochlea (P28 and P32), S100β expression declined in both Deiter’s and pillar cells. The dynamic spatiotemporal changes in S100β expression during cochlear ontogeny suggest its role in cochlear development and hearing function.

Dishevelled (Dvl) proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3(-/-) mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3(-/-) and LtapLp/+ mutants, Dvl3(+/-);LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant.

In the developing nervous system, axons navigate through complex terrains that change depending on when and where outgrowth begins. For instance, in the developing cochlea, spiral ganglion neurons extend their peripheral processes through a growing and heterogeneous environment en route to their final targets, the hair cells. Although the basic principles of axon guidance are well established, it remains unclear how axons adjust strategies over time and space. Here, we show that neurons with different positions in the spiral ganglion employ different guidance mechanisms, with evidence for both glia-guided growth and fasciculation along a neuronal scaffold. Processes from neurons in the rear of the ganglion are more directed and grow faster than those from neurons at the border of the ganglion. Further, processes at the wavefront grow more efficiently when in contact with glial precursors growing ahead of them. These findings suggest a tiered mechanism for reliable axon guidance. In developing embryos, axons grow through complex and dynamic terrains. Here, the authors show that spiral ganglion neurons in the developing mouse cochlea extend leading axons that interact with a scaffold of glial precursors, with follower axons fasciculating on top.