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Developmental profiling of spiral ganglion neurons reveals insights into auditory circuit assembly.

ABSTRACT: The sense of hearing depends on the faithful transmission of sound information from the ear to the brain by spiral ganglion (SG) neurons. However, how SG neurons develop the connections and properties that underlie auditory processing is largely unknown. We catalogued gene expression in mouse SG neurons from embryonic day 12, when SG neurons first extend projections, up until postnatal day 15, after the onset of hearing. For comparison, we also analyzed the closely related vestibular ganglion (VG). Gene ontology analysis confirmed enriched expression of genes associated with gene regulation and neurite outgrowth at early stages, with the SG and VG often expressing different members of the same gene family. At later stages, the neurons transcribe more genes related to mature function, and exhibit a dramatic increase in immune gene expression. Comparisons of the two populations revealed enhanced expression of TGFβ pathway components in SG neurons and established new markers that consistently distinguish auditory and vestibular neurons. Unexpectedly, we found that Gata3, a transcription factor commonly associated with auditory development, is also expressed in VG neurons at early stages. We therefore defined new cohorts of transcription factors and axon guidance molecules that are uniquely expressed in SG neurons and may drive auditory-specific aspects of their differentiation and wiring. We show that one of these molecules, the receptor guanylyl cyclase Npr2, is required for bifurcation of the SG central axon. Hence, our dataset provides a useful resource for uncovering the molecular basis of specific auditory circuit assembly events.

SUBMITTER: Lu CC

PROVIDER: S-EPMC3167573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Developmental profiling of spiral ganglion neurons reveals insights into auditory circuit assembly

Project description:The sense of hearing depends on the faithful transmission of sound information from the ear to the brain by spiral ganglion (SG) neurons. However, how SG neurons develop the connections and properties that underlie auditory processing is largely unknown. We catalogued gene expression in mouse SG neurons at six developmental stages, ranging from embryonic day 12 (E12), when SG neurons first extend projections, up until postnatal day 15 (P15), after the onset of hearing. For comparison, we also analyzed the closely-related vestibular ganglion (VG) at the same time points. To identify genes involved in SG axon guidance and branching, target selection, synaptogenesis, synaptic refinement, and synaptic function, we collected SG at E12 and E13, E16, P0, P6, and P15. We also collected VG at the same time points. For E12 and E13 time points, SG and VG were microdissected from Rnx-cre; Z/EG embryos, which express GFP in the VG. E16-P15 VG was also isolated by microdissection from Rnx-cre; Z/EG animals. E16-P15 SG neurons were isolated by FACS sorting dissociated cochlea from Mafb-GFP animals.

2011-07-14 | E-GEOD-29766 | biostudies-arrayexpress

Developmental profiling of spiral ganglion neurons reveals insights into auditory circuit assembly

2011-07-15 | GSE29766 | GEO

Unmyelinated auditory type I spiral ganglion neurons in congenic Ly5.1 mice.

Project description:With the exception of humans, the somata of type I spiral ganglion neurons (SGNs) of most mammalian species are heavily myelinated. In an earlier study, we used Ly5.1 congenic mice as transplant recipients to investigate the role of hematopoietic stem cells in the adult mouse inner ear. An unanticipated finding was that a large percentage of the SGNs in this strain were unmyelinated. Further characterization of the auditory phenotype of young adult Ly5.1 mice in the present study revealed several unusual characteristics, including 1) large aggregates of unmyelinated SGNs in the apical and middle turns, 2) symmetrical junction-like contacts between the unmyelinated neurons, 3) abnormal expression patterns for CNPase and connexin 29 in the SGN clusters, 4) reduced SGN density in the basal cochlea without a corresponding loss of sensory hair cells, 5) significantly delayed auditory brainstem response (ABR) wave I latencies at low and middle frequencies compared with control mice with similar ABR threshold, and 6) elevated ABR thresholds and deceased wave I amplitudes at high frequencies. Taken together, these data suggest a defect in Schwann cells that leads to incomplete myelinization of SGNs during cochlear development. The Ly5.1 mouse strain appears to be the only rodent model so far identified with a high degree of the "human-like" feature of unmyelinated SGNs that aggregate into neural clusters. Thus, this strain may provide a suitable animal platform for modeling human auditory information processing such as synchronous neural activity and other auditory response properties.

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RNAseq of A/J mice spiral ganglion derived neurospheres vs differentiated auditory neurons

Project description:Sphere-forming progenitor cells can be isolated from the fetal and adult mammalian inner ear and give rise to inner ear specific cell types in vitro. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit nearly unlimited intrinsic self-renewal properties (beyond 40 passages). At any passage, phoenix spheres can be efficiently differentiated by withdrawing growth factors into mature spiral ganglion cells, expressing both neurons and glial cells phenotypic markers and exhibiting similar functional properties as mouse spiral ganglion explants and human sphere-derived spiral ganglion cells. The present dataset includes RNAseq-based transcriptome analysis of phoenix auditory neurons following 7 days of differentiation. mRNA levels in differentiated cells are expressed relatively to neuroprogenitor spheres of equivalent passage (paired samples at passage 12, 21 and 36)

2020-08-29 | E-MTAB-9441 | biostudies-arrayexpress

Developmental Changes in <i>Peripherin-</i>eGFP Expression in Spiral Ganglion Neurons.

Project description:The two types of spiral ganglion neurons (SGNs), types I and II, innervate inner hair cells and outer hair cells, respectively, within the mammalian cochlea and send another process back to cochlear nuclei in the hindbrain. Studying these two neuronal types has been made easier with the identification of unique molecular markers. One of these markers, peripherin, was shown using antibodies to be present in all SGNs initially but becomes specific to type II SGNs during maturation. We used mice with fluorescently labeled peripherin (Prph-eGFP) to examine peripherin expression in SGNs during development and in aged mice. Using these mice, we confirm the initial expression of Prph-eGFP in both types I and II neurons and eventual restriction to only type II perikarya shortly after birth. However, while Prph-eGFP is uniquely expressed within type II cell bodies by P8, both types I and II peripheral and central processes continue to express Prph-eGFP for some time before becoming downregulated. Only at P30 was there selective type II Prph-eGFP expression in central but not peripheral processes. By 9 months, only the type II cell bodies and more distal central processes retain Prph-eGFP expression. Our results show that Prph-eGFP is a reliable marker for type II SGN cell bodies beyond P8; however, it is not generally a suitable marker for type II processes, except for central processes beyond P30. How the changes in Prph-eGFP expression relate to subsequent protein expression remains to be explored.

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Atoh1-lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei.

Project description:Atoh1 is a basic helix-loop-helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used the Cre-loxP system and two Cre-driver lines (Egr2(Cre) and Hoxb1(Cre)) to delete Atoh1 from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). Adult Atoh1-conditional knock-out mice (Atoh1(CKO)) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition, Egr2; Atoh1(CKO) mice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.

| S-EPMC2743121 | biostudies-literature

Intrinsically Self-renewing Neuroprogenitors From the A/J Mouse Spiral Ganglion as Virtually Unlimited Source of Mature Auditory Neurons.

Project description:Nearly 460 million individuals are affected by sensorineural hearing loss (SNHL), one of the most common human sensory disorders. In mammals, hearing loss is permanent due to the lack of efficient regenerative capacity of the sensory epithelia and spiral ganglion neurons (SGN). Sphere-forming progenitor cells can be isolated from the mammalian inner ear and give rise to inner ear specific cell types in vitro. However, the self-renewing capacities of auditory progenitor cells from the sensory and neuronal compartment are limited to few passages, even after adding powerful growth factor cocktails. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit robust intrinsic self-renewal properties beyond 40 passages. At any passage or freezing-thawing cycle, phoenix spheres can be efficiently differentiated into mature spiral ganglion cells by withdrawing growth factors. The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.

| S-EPMC7761749 | biostudies-literature

Differentiation of Spiral Ganglion Neurons from Human Dental Pulp Stem Cells: A Further Step towards Autologous Auditory Nerve Recovery.

Project description:The degeneration of spiral ganglion neurons (SGNs), which convey auditory signals from hair cells to the brain, can be a primary cause of sensorineural hearing loss (SNHL) or can occur secondary to hair cell loss. Emerging therapies for SNHL include the replacement of damaged SGNs using stem cell-derived otic neuronal progenitors (ONPs). However, the availability of renewable, accessible, and patient-matched sources of human stem cells is a prerequisite for successful replacement of the auditory nerve. In this study, we derived ONP and SGN-like cells by a reliable and reproducible stepwise guidance differentiation procedure of self-renewing human dental pulp stem cells (hDPSCs). This in vitro differentiation protocol relies on the modulation of BMP and TGFβ pathways using a free-floating 3D neurosphere method, followed by differentiation on a Geltrex-coated surface using two culture paradigms to modulate the major factors and pathways involved in early otic neurogenesis. Gene and protein expression analyses revealed efficient induction of a comprehensive panel of known ONP and SGN-like cell markers during the time course of hDPSCs differentiation. Atomic force microscopy revealed that hDPSC-derived SGN-like cells exhibit similar nanomechanical properties as their in vivo SGN counterparts. Furthermore, spiral ganglion neurons from newborn rats come in close contact with hDPSC-derived ONPs 5 days after co-culturing. Our data demonstrate the capability of hDPSCs to generate SGN-like neurons with specific lineage marker expression, bipolar morphology, and the nanomechanical characteristics of SGNs, suggesting that the neurons could be used for next-generation cochlear implants and/or inner ear cell-based strategies for SNHL.

| S-EPMC11354632 | biostudies-literature

Auditory Neuropathy after Damage to Cochlear Spiral Ganglion Neurons in Mice Resulting from Conditional Expression of Diphtheria Toxin Receptors.

Project description:Auditory neuropathy (AN) is a hearing disorder characterized by normal cochlear amplification to sound but poor temporal processing and auditory perception in noisy backgrounds. These deficits likely result from impairments in auditory neural synchrony; such dyssynchrony of the neural responses has been linked to demyelination of auditory nerve fibers. However, no appropriate animal models are currently available that mimic this pathology. In this study, Cre-inducible diphtheria toxin receptor (iDTR +/+ ) mice were cross-mated with mice containing Cre (Bhlhb5-Cre +/- ) specific to spiral ganglion neurons (SGNs). In double-positive offspring mice, the injection of diphtheria toxin (DT) led to a 30-40% rate of death for SGNs, but no hair cell damage. Demyelination types of pathologies were observed around the surviving SGNs and their fibers, many of which were distorted in shape. Correspondingly, a significant reduction in response synchrony to amplitude modulation was observed in this group of animals compared to the controls, which had a Cre- genotype. Taken together, our results suggest that SGN damage following the injection of DT in mice with Bhlhb5-Cre +/- and iDTR +/- is likely to be a good AN model of demyelination.

| S-EPMC5527113 | biostudies-literature

Transcriptional profiling of cochlear spiral ganglion neurons and lateral wall cells

Project description:In order to characterize the response to noise of various cell types in the inner ear, the cochleae from wild-type mice, naive or subjected to a 2h, 105 dB SPL noise insult, were dissected out. To further examine spiral ganglion neurons in more detail, non-neuronal populations were removed in one set of samples. In another set of samples, the lateral wall tissue was isolated to better understand how cells from the stria respond to noise insults. The resulting tissue was then dissociated to obtain a single cell suspension, and profiled by single cell RNA-seq.

2021-09-08 | GSE168041 | GEO

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