Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses

Johnson, Stuart L.; Franz, Christoph; Kuhn, Stephanie; Furness, David N.; Rüttiger, Lukas; Münkner, Stefan; Rivolta, Marcelo N.; Seward, Elizabeth P.; Herschman, Harvey R.; Engel, Jutta; Knipper, Marlies; Marcotti, Walter

doi:10.1038/nn.2456

Cited by 111 publications

(182 citation statements)

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“…These findings suggest that in the diminuendo mutant, the biophysical properties of IHCs and OHCs do not develop further than the late embryonic/early postnatal stage, resulting in a coordinated general halt in their physiological development. (29,30), a process that requires synaptotagmin IV (31). We found that the mutation in Mir96 interfered with the normal IHC synaptic development.…”

Section: +mentioning

confidence: 78%

“…The onset of functional maturity in OHCs and IHCs occurs at about P8 and P12, respectively, with the acquisition and/or elimination of different ion channels (25,26). Postnatal hair cell maturation also includes expression of specialized membrane proteins such as prestin (3), changes in the structural and functional characteristics of ribbon synapses (30)(31)(32), and a major refinement in the neuronal connections within the mammalian cochlea (33). We have shown that the mutation in Mir96 prevents, from around birth, any further progression in the development of the hair cell stereocilia bundle morphology, cell length, ribbon synapses, and innervation pattern.…”

Section: Discussionmentioning

confidence: 99%

“…3 C and D). The consequence of the immature I Ca and ΔC m in adult Dmdo/Dmdo IHCs was that the exocytotic Ca 2+ dependence, defined as the change in ΔC m as a function of I Ca and measured using the synaptic transfer function (29)(30)(31), was significantly less linear (power of ∼3.4 ± 0.4, n = 8) than that in heterozygous (power of 1.9 ± 0.2, n = 7; P < 0.01) and control (power of 1.2 ± 0.2, n = 7; P < 0.001; Fig. 3E) IHCs.…”

Section: +mentioning

confidence: 99%

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miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells

Kuhn

Johnson

Furness

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNAs (miRNAs) are small noncoding RNAs able to regulate a broad range of protein-coding genes involved in many biological processes. miR-96 is a sensory organ-specific miRNA expressed in the mammalian cochlea during development. Mutations in miR-96 cause nonsyndromic progressive hearing loss in humans and mice. The mouse mutant diminuendo has a single base change in the seed region of the Mir96 gene leading to widespread changes in the expression of many genes. We have used this mutant to explore the role of miR-96 in the maturation of the auditory organ. We found that the physiological development of mutant sensory hair cells is arrested at around the day of birth, before their biophysical differentiation into inner and outer hair cells. Moreover, maturation of the hair cell stereocilia bundle and remodelling of auditory nerve connections within the cochlea fail to occur in miR-96 mutants. We conclude that miR-96 regulates the progression of the physiological and morphological differentiation of cochlear hair cells and, as such, coordinates one of the most distinctive functional refinements of the mammalian auditory system. deafness | mouse model | sensory system | currents | action potentials I n the mammalian cochlea, inner hair cells (IHCs) and outer hair cells (OHCs) transduce sound into electrical responses. IHCs are the primary sensory receptors that relay sound stimuli to the brain with high temporal precision via the release of neurotransmitter from their ribbon synapses onto type I spiral ganglion neurons (1). Synaptic ribbons are specialized organelles able to tether a large number of synaptic vesicles at the cell's active zones and are thought to allow sensory cells to mediate high rates of sustained synaptic transmission, coordinated release of multiple vesicles, and temporally precise transfer of information (2). OHCs provide electromechanical amplification of the cochlear partition to enhance the sensitivity and frequency selectivity of the mammalian cochlea via voltage-dependent electromotility, which is mediated by the motor protein prestin (3) and modulated by the inhibitory efferent cholinergic system (4). Before sound-induced responses begin at the onset of hearing, which occurs at around postnatal day 12 (P12) in most rodents, hair cells undergo a precise developmental program. Although hair cell maturation is known to be influenced by many proteins (5-9), we know little about the mechanisms underlying their biophysical and morphological development, especially those involved in the functional differentiation of IHCs and OHCs that occurs from around birth (10).MicroRNAs (miRNAs) regulate posttranscriptional gene expression programs by decreasing the level of target mRNA in mammals (11) and are involved in tissue development, cell fate specification, morphogenesis, and a range of diseases (12-16). Members of the miR-183 family (miR-96, miR-182, and miR-183) are specific to sensory organs (17, 18) and are highly expressed in the inner ear (19,20), eye (17), and nose (21). In the inner ear...

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Section: +mentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: +mentioning

confidence: 99%

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miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells

Kuhn

Johnson

Furness

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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105

123

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“…Many sensory neurons do not fire action potentials in response to stimuli. Graded release of neurotransmitters is widely used in sensory neurons, including photoreceptor cells 55 , auditory hair cells 56 and olfactory neurons 57 . In C. elegans, AWC neurons have non-spiking, have tonic neurotransmitter release at rest and respond to excitatory or inhibitory inputs with graded changes in membrane potential and transmitter release 57 .…”

Section: Discussionmentioning

confidence: 99%

Reciprocal inhibition between sensory ASH and ASI neurons modulates nociception and avoidance in Caenorhabditis elegans

et al. 2015

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Sensory modulation is essential for animal sensations, behaviours and survival. Peripheral modulations of nociceptive sensations and aversive behaviours are poorly understood. Here we identify a biased cross-inhibitory neural circuit between ASH and ASI sensory neurons. This inhibition is essential to drive normal adaptive avoidance of a CuSO 4 (Cu 2 þ ) challenge in Caenorhabditis elegans. In the circuit, ASHs respond to Cu 2 þ robustly and suppress ASIs via electro-synaptically exciting octopaminergic RIC interneurons, which release octopamine (OA), and neuroendocrinally inhibit ASI by acting on the SER-3 receptor. In addition, ASIs sense Cu 2 þ and permit a rapid onset of Cu 2 þ -evoked responses in Cu 2 þ -sensitive ADF neurons via neuropeptides possibly, to inhibit ASHs. ADFs function as interneurons to mediate ASI inhibition of ASHs by releasing serotonin (5-HT) that binds with the SER-5 receptor on ASHs. This elaborate modulation among sensory neurons via reciprocal inhibition fine-tunes the nociception and avoidance behaviour.

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“…46,47 Despite the lack of Ca 2+ binding by the Syt IV and Syt XI C2A domains, 46 Syt IV facilitates regulated exocytosis in neurons, astrocytes and endocrine cells. 28,[48][49][50] Similarly, Syt XI-containing vesicles undergo depolarization-triggered exocytosis in neurons. 42 Similar to neuronal lysosomes, 51 Syt XI-containing exocytic vesicles in neurons are acidic in nature and localize to dendrites.…”

Section: Discussionmentioning

confidence: 99%

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

et al. 2015

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Astrocytes are known to facilitate repair following brain injury; however, little is known about how injured astrocytes repair themselves. Repair of cell membrane injury requires Ca 2+ -triggered vesicle exocytosis. In astrocytes, lysosomes are the main Ca 2+ -regulated exocytic vesicles. Here we show that astrocyte cell membrane injury results in a large and rapid calcium increase. This triggers robust lysosome exocytosis where the fusing lysosomes release all luminal contents and merge fully with the plasma membrane. In contrast to this, receptor stimulation produces a small sustained calcium increase, which is associated with partial release of the lysosomal luminal content, and the lysosome membrane does not merge into the plasma membrane. In most cells, lysosomes express the synaptotagmin (Syt) isoform Syt VII; however, this isoform is not present on astrocyte lysosomes and exogenous expression of Syt VII on lysosome inhibits their exocytosis. Deletion of one of the most abundant Syt isoform in astrocyte -Syt XI -suppresses astrocyte lysosome exocytosis. This identifies lysosome as Syt XI-regulated exocytic vesicle in astrocytes. Further, inhibition of lysosome exocytosis (by Syt XI depletion or Syt VII expression) prevents repair of injured astrocytes. These results identify the lysosomes and Syt XI as the sub-cellular and molecular regulators, respectively of astrocyte cell membrane repair.

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Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses

Cited by 111 publications

References 52 publications

miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells

miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells

Reciprocal inhibition between sensory ASH and ASI neurons modulates nociception and avoidance in Caenorhabditis elegans

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

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