scholarly journals Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

2019 ◽  
Author(s):  
Travis A. Babola ◽  
Calvin J. Kersbergen ◽  
Han Chin Wang ◽  
Dwight E. Bergles
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Extracellular Space ◽  
Molecular Mechanisms ◽  
Purinergic Signaling ◽  
Burst Firing ◽  
Supporting Cells ◽  
Cell Excitability ◽  
Sensory Pathways ◽  
Cochlear Supporting Cells

AbstractNeurons in developing sensory pathways exhibit spontaneous bursts of electrical activity that are critical for survival, maturation and circuit refinement. In the auditory system, intrinsically generated activity arises within the cochlea, but the molecular mechanisms that initiate this activity remain poorly understood. We show that burst firing of mouse inner hair cells prior to hearing onset requires P2RY1 autoreceptors expressed by inner supporting cells. P2RY1 activation triggers K+ efflux and depolarization of hair cells, as well as osmotic shrinkage of supporting cells that dramatically increased the extracellular space and speed of K+ redistribution. Pharmacological inhibition or genetic disruption of P2RY1 suppressed neuronal burst firing by reducing K+ release, but unexpectedly enhanced their tonic firing, as water resorption by supporting cells reduced the extracellular space, slowing K+ clearance. These studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by controlling the volume of the extracellular space.

scholarly journals Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Travis A Babola ◽  
Calvin J Kersbergen ◽  
Han Chin Wang ◽  
Dwight E Bergles
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Extracellular Space ◽  
Molecular Mechanisms ◽  
Purinergic Signaling ◽  
Burst Firing ◽  
Supporting Cells ◽  
Cell Excitability ◽  
Sensory Pathways ◽  
Cochlear Supporting Cells

Neurons in developing sensory pathways exhibit spontaneous bursts of electrical activity that are critical for survival, maturation and circuit refinement. In the auditory system, intrinsically generated activity arises within the cochlea, but the molecular mechanisms that initiate this activity remain poorly understood. We show that burst firing of mouse inner hair cells prior to hearing onset requires P2RY1 autoreceptors expressed by inner supporting cells. P2RY1 activation triggers K+ efflux and depolarization of hair cells, as well as osmotic shrinkage of supporting cells that dramatically increased the extracellular space and speed of K+ redistribution. Pharmacological inhibition or genetic disruption of P2RY1 suppressed neuronal burst firing by reducing K+ release, but unexpectedly enhanced their tonic firing, as water resorption by supporting cells reduced the extracellular space, leading to K+ accumulation. These studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by controlling the volume of the extracellular space.

scholarly journals Cochlear organoids reveal epigenetic and transcriptional programs of postnatal hair cell differentiation from supporting cells

2021 ◽  
Author(s):  
Gurmannat Kalra ◽  
Danielle Lenz ◽  
Dunia Abdul-Aziz ◽  
Craig Hanna ◽  
Brian Herb ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Regulatory Networks ◽  
Hair Cell Regeneration ◽  
Cell Fates ◽  
Supporting Cells ◽  
Enhancer Binding Protein ◽  
Full Picture ◽  
Hair Cell Differentiation ◽  
Cochlear Supporting Cells

We explored the transcriptional and epigenetic programs underlying the differentiation of hair cells from postnatal progenitor cells in cochlear organoids. Heterogeneity in the cells including cells with the transcriptional signatures of mature hair cells allowed a full picture of possible cell fates. Construction of trajectories identified Lgr5+ cells as progenitors for hair cells and the genomic data revealed gene regulatory networks leading to hair cells. We validated these networks, demonstrating dynamic changes both in expression and predicted binding sites of these transcription factors during organoid differentiation. We identified known regulators of hair cell development, Atoh1, Pou4f3, and Gfi1, and predicted novel regulatory factors, Tcf4, an E-protein and heterodimerization partner of Atoh1, and Ddit3, a CCAAT/enhancer-binding protein (C/EBP) that represses Hes1 and activates transcription of Wnt signaling-related genes. Deciphering the signals for hair cell regeneration from mammalian cochlear supporting cells reveals candidates for HC regeneration which is limited in the adult.

Molecular Mechanisms of Mechanoreceptor Adaptation

Physiology ◽  
1994 ◽  
Vol 9 (2) ◽  
pp. 53-59
Author(s):  
OP Hamill ◽  
DW, McBride
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Molecular Mechanisms ◽  
Mechanosensitive Channel ◽  
Cell Adaptation ◽  
Stimulus Domain ◽  
Dynamic Sensitivity ◽  
Voltage Dependent ◽  
Channel Currents

Mechanoreceptor adaptation to maintained stimulation serves to maximize dynamic sensitivity over a broad stimulus domain. Mechanosensitive channel currents in hair cells and oocytes show similar voltage-dependent adaptation. However, in the hair cell, adaptation appears dependent on Ca2+ influx, whereas in the oocyte, it is intrinsically voltage sensitive.

scholarly journals LIN28B/let-7control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

2020 ◽  
Vol 117 (36) ◽  
pp. 22225-22236
Author(s):  
Xiao-Jun Li ◽  
Angelika Doetzlhofer
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Rna Binding ◽  
Mammalian Target Of Rapamycin ◽  
Cell Loss ◽  
Supporting Cell ◽  
Dependent Manner ◽  
Cell Plasticity ◽  
Supporting Cells ◽  
Cochlear Hair Cells

Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mammalian target of rapamycin (mTOR) activity. Employing murine cochlear organoid and explant cultures to model mitotic and nonmitotic mechanisms of hair cell generation, we show that loss of LIN28B function, due to its conditional deletion, or due to overexpression of the antagonistic miRNAlet-7g, suppressed Akt-mTOR complex 1 (mTORC1) activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and nonmitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner.

scholarly journals Hearing Loss in Neurological Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Siyu Li ◽  
Cheng Cheng ◽  
Ling Lu ◽  
Xiaofeng Ma ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Relevant Literature ◽  
Autism Spectrum ◽  
Supporting Cells ◽  
Cochlear Hair Cells ◽  
Wide Range ◽  
Histological Characteristics

Sensorineural hearing loss (SNHL) affects approximately 466 million people worldwide, which is projected to reach 900 million by 2050. Its histological characteristics are lesions in cochlear hair cells, supporting cells, and auditory nerve endings. Neurological disorders cover a wide range of diseases affecting the nervous system, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), autism spectrum disorder (ASD), etc. Many studies have revealed that neurological disorders manifest with hearing loss, in addition to typical nervous symptoms. The prevalence, manifestations, and neuropathological mechanisms underlying vary among different diseases. In this review, we discuss the relevant literature, from clinical trials to research mice models, to provide an overview of auditory dysfunctions in the most common neurological disorders, particularly those associated with hearing loss, and to explain their underlying pathological and molecular mechanisms.

Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells

Nature ◽  
2006 ◽  
Vol 441 (7096) ◽  
pp. 984-987 ◽  
Author(s):  
Patricia M. White ◽  
Angelika Doetzlhofer ◽  
Yun Shain Lee ◽  
Andrew K. Groves ◽  
Neil Segil
Keyword(s):  
Hair Cells ◽  
Supporting Cells ◽  
Cochlear Supporting Cells

scholarly journals Cochlear supporting cells function as macrophage-like cells and protect audiosensory receptor hair cells from pathogens

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yushi Hayashi ◽  
Hidenori Suzuki ◽  
Wataru Nakajima ◽  
Ikuno Uehara ◽  
Atsuko Tanimura ◽  
...  
Keyword(s):  
Hair Cells ◽  
Supporting Cells ◽  
Cochlear Supporting Cells
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