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Trends in Neurosciences Jun 2019Sensory hair cells of the inner ear are exposed to continuous mechanical stress, causing damage over time. The maintenance of hair cells is further challenged by damage... (Review)
Review
Sensory hair cells of the inner ear are exposed to continuous mechanical stress, causing damage over time. The maintenance of hair cells is further challenged by damage from a variety of other ototoxic factors, including loud noise, aging, genetic defects, and ototoxic drugs. This damage can manifest in many forms, from dysfunction of the hair cell mechanotransduction complex to loss of specialized ribbon synapses, and may even result in hair cell death. Given that mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. Here, we discuss how several key hair cell structures can be damaged, and what is known about how they are repaired.
Topics: Animals; Hair Cells, Auditory, Inner; Humans
PubMed: 30992136
DOI: 10.1016/j.tins.2019.03.006 -
Science (New York, N.Y.) Aug 2020Although Huntington's disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest...
Although Huntington's disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington's disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carried the Huntington's disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington's disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington's disease thus has a neurodevelopmental component and is not solely a degenerative disease.
Topics: Animals; Cell Cycle; Endosomes; Fetus; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Mutant Strains; Mitosis; Mutation; Nervous System; Neuroepithelial Cells; Tight Junctions; Zonula Occludens-1 Protein
PubMed: 32675289
DOI: 10.1126/science.aax3338 -
Nature Protocols Oct 2014Human brain development exhibits several unique aspects, such as increased complexity and expansion of neuronal output, that have proven difficult to study in model...
Human brain development exhibits several unique aspects, such as increased complexity and expansion of neuronal output, that have proven difficult to study in model organisms. As a result, in vitro approaches to model human brain development and disease are an intense area of research. Here we describe a recently established protocol for generating 3D brain tissue, so-called cerebral organoids, which closely mimics the endogenous developmental program. This method can easily be implemented in a standard tissue culture room and can give rise to developing cerebral cortex, ventral telencephalon, choroid plexus and retinal identities, among others, within 1-2 months. This straightforward protocol can be applied to developmental studies, as well as to the study of a variety of human brain diseases. Furthermore, as organoids can be maintained for more than 1 year in long-term culture, they also have the potential to model later events such as neuronal maturation and survival.
Topics: Brain; Humans; Neuroepithelial Cells; Organoids; Pluripotent Stem Cells; Time Factors; Tissue Culture Techniques
PubMed: 25188634
DOI: 10.1038/nprot.2014.158 -
Nature Neuroscience Mar 2022The mammalian brain contains many specialized cells that develop from a thin sheet of neuroepithelial progenitor cells. Single-cell transcriptomics revealed hundreds of...
The mammalian brain contains many specialized cells that develop from a thin sheet of neuroepithelial progenitor cells. Single-cell transcriptomics revealed hundreds of molecularly diverse cell types in the nervous system, but the lineage relationships between mature cell types and progenitor cells are not well understood. Here we show in vivo barcoding of early progenitors to simultaneously profile cell phenotypes and clonal relations in the mouse brain using single-cell and spatial transcriptomics. By reconstructing thousands of clones, we discovered fate-restricted progenitor cells in the mouse hippocampal neuroepithelium and show that microglia are derived from few primitive myeloid precursors that massively expand to generate widely dispersed progeny. We combined spatial transcriptomics with clonal barcoding and disentangled migration patterns of clonally related cells in densely labeled tissue sections. Our approach enables high-throughput dense reconstruction of cell phenotypes and clonal relations at the single-cell and tissue level in individual animals and provides an integrated approach for understanding tissue architecture.
Topics: Animals; Brain; Cell Differentiation; Clone Cells; Mammals; Mice; Neuroepithelial Cells; Stem Cells; Transcriptome
PubMed: 35210624
DOI: 10.1038/s41593-022-01011-x -
Nature Neuroscience Apr 2021The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex....
The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.
Topics: Animals; Cerebral Cortex; Ependymoglial Cells; Humans; Neural Stem Cells; Neuroepithelial Cells; Neurogenesis; Single-Cell Analysis
PubMed: 33723434
DOI: 10.1038/s41593-020-00794-1 -
Nature Communications May 2020Mammalian 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,...
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.
Topics: Animals; Cells, Cultured; Cochlea; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hair Cells, Auditory; Hair Cells, Auditory, Inner; Hair Cells, Auditory, Outer; Mice; Organ of Corti; Single-Cell Analysis; Time Factors
PubMed: 32404924
DOI: 10.1038/s41467-020-16113-y -
Scientific Reports Jun 2022The fish gill is a multifunctional organ involved in numerous physiological processes, such as gas exchange and sensing of hypoxia by respiratory chemoreceptors, called...
The fish gill is a multifunctional organ involved in numerous physiological processes, such as gas exchange and sensing of hypoxia by respiratory chemoreceptors, called neuroepithelial cells (NECs). Many studies have focused on zebrafish (Danio rerio) to investigate the structure, function and development of the gills, yet the transcriptomic profile of most gill cells remains obscure. We present the results of a comprehensive transcriptomic analysis of the gills of zebrafish using single-cell RNA sequencing (scRNA-seq). Gill cells from ETvmat2:EGFP zebrafish were individually labelled before scRNA-seq library construction using 10× Genomics Chromium technology. 12,819 cells were sequenced with an average depth of over 27,000 reads per cell. We identified a median of 485 genes per cell and 16 cell clusters, including NECs, neurons, pavement cells, endothelial cells and mitochondrion-rich cells. The identity of NECs was confirmed by expression of slc18a2, encoding the vesicular monoamine transporter, Vmat2. Highly differentially-expressed genes in NECs included tph1a, encoding tryptophan hydroxylase, sv2 (synaptic vesicle protein), and proteins implicated in O sensing (ndufa4l2a, cox8al and epas1a). In addition, NECs and neurons expressed genes encoding transmembrane receptors for serotonergic, cholinergic or dopaminergic neurotransmission. Differential expression analysis showed a clear shift in the transcriptome of NECs following 14 days of acclimation to hypoxia. NECs in the hypoxia group showed high expression of genes involved in cell cycle control and proliferation. The present article provides a complete cell atlas for the zebrafish gill and serves as a platform for future studies investigating the molecular biology and physiology of this organ.
Topics: Animals; Endothelial Cells; Gills; Hypoxia; Neuroepithelial Cells; Oxygen; Single-Cell Analysis; Transcriptome; Zebrafish
PubMed: 35710785
DOI: 10.1038/s41598-022-13693-1 -
Cold Spring Harbor Perspectives in... May 2019Cholinergic efferent neurons originating in the brainstem innervate the acoustico-lateralis organs (inner ear, lateral line) of vertebrates. These release acetylcholine... (Review)
Review
Cholinergic efferent neurons originating in the brainstem innervate the acoustico-lateralis organs (inner ear, lateral line) of vertebrates. These release acetylcholine (ACh) to inhibit hair cells through activation of calcium-dependent potassium channels. In the mammalian cochlea, ACh shunts and suppresses outer hair cell (OHC) electromotility, reducing the essential amplification of basilar membrane motion. Consequently, medial olivocochlear neurons that inhibit OHCs reduce the sensitivity and frequency selectivity of afferent neurons driven by cochlear vibration of inner hair cells (IHCs). The cholinergic synapse on hair cells involves an unusual ionotropic ACh receptor, and a near-membrane postsynaptic cistern. Lateral olivocochlear (LOC) neurons modulate type I afferents by still-to-be-defined synaptic mechanisms. Olivocochlear neurons can be activated by a reflex arc that includes the auditory nerve and projections from the cochlear nucleus. They are also subject to modulation by higher-order central auditory interneurons. Through its actions on cochlear hair cells, afferent neurons, and higher centers, the olivocochlear system protects against age-related and noise-induced hearing loss, improves signal coding in noise under certain conditions, modulates selective attention to sensory stimuli, and influences sound localization.
Topics: Animals; Cochlea; Efferent Pathways; Hair Cells, Auditory, Inner; Hair Cells, Auditory, Outer; Humans; Ion Channels; Mice; Mice, Knockout; Neurotransmitter Agents; Synapses; Synaptic Transmission
PubMed: 30082454
DOI: 10.1101/cshperspect.a033530 -
Neuroscience Bulletin Jan 2024Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main... (Review)
Review
Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic.
Topics: Infant, Newborn; Humans; Hair Cells, Auditory, Inner; Ear, Inner; Hair Cells, Auditory; Regeneration; Stem Cells
PubMed: 37787875
DOI: 10.1007/s12264-023-01130-w -
Physiological Research May 2018This review is focused on the unusual composition of the endolymph of the inner ear and its function in mechanoelectrical transduction. The role of K(+) and Ca(2+) in... (Review)
Review
This review is focused on the unusual composition of the endolymph of the inner ear and its function in mechanoelectrical transduction. The role of K(+) and Ca(2+) in excitatory influx, the very low Na(+), Ca(2+) and Mg(2+) concentrations of endolymph, stereocilia structure of hair cells and some proteins involved in mechanosensory signal transduction with emphasis on auditory receptors are presented and analyzed in more details. An alternative hypothetical model of ciliary structure and endolymph with a 'normal' composition is discussed. It is concluded that the unique endolymph cation content is more than an energy saving mechanism that avoids disturbing circulatory vibrations to achieve a much better mechanosensory resolution. It is the only possible way to fulfil the requirements for a precise ciliary mechanoelectrical transduction in conditions where pressure events with quite diverse amplitudes and duration are transformed into adequate hair cell membrane depolarizations, which are regulated by a sensitive Ca(2+)-dependent feedback tuning.
Topics: Animals; Ear, Inner; Endolymph; Hair Cells, Auditory, Inner; Humans; Mechanotransduction, Cellular
PubMed: 29303598
DOI: 10.33549/physiolres.933684