Identification and Immunocytochemical Characterization of Piccolino, a Novel Piccolo Splice Variant Selectively Expressed at Sensory Ribbon Synapses of the Eye and Ear

Regus-Leidig, Hanna; Ott, Corinna; Löhner, Martina; Atorf, Jenny; Fuchs, Michaela; Sedmak, Tina; Kremers, Jan; Fejtová, Anna; Gundelfinger, Eckart D.; Brandstätter, Johann Helmut

doi:10.1371/journal.pone.0070373

Cited by 65 publications

(105 citation statements)

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“…13 For example, the retinal photoreceptor and bipolar cell ribbon synapses express a unique Pclo isoform that is not affected by the absence of exon 14. 18 This could, in part, explain the phenotypic difference between mice and humans, and raises the possibility that different PCLO isoforms have tissue-specific roles in the human CNS.…”

Section: Resultsmentioning

confidence: 99%

Loss of PCLO function underlies pontocerebellar hypoplasia type III

et al. 2015

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Objective: To identify the genetic cause of pontocerebellar hypoplasia type III (PCH3). Methods:We studied the original reported pedigree of PCH3 and performed genetic analysis including genome-wide single nucleotide polymorphism genotyping, linkage analysis, wholeexome sequencing, and Sanger sequencing. Human fetal brain RNA sequencing data were then analyzed for the identified candidate gene. Results:The affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. Genome-wide single nucleotide polymorphism analysis confirmed the linkage to chromosome 7q we previously reported, and showed no other genomic areas of linkage. Whole-exome sequencing of 2 affected individuals identified a shared homozygous, nonsense variant in the PCLO (piccolo) gene. This variant segregated with the disease phenotype in the pedigree was rare in the population and was predicted to eliminate the PDZ and C2 domains in the C-terminus of the protein. RNA sequencing data of human fetal brain showed that PCLO was moderately expressed in the developing cerebral cortex.Conclusions: Here, we show that a homozygous, nonsense PCLO mutation underlies the autosomal recessive neurodegenerative disorder, PCH3. PCLO is a component of the presynaptic cytoskeletal matrix, and is thought to be involved in regulation of presynaptic proteins and synaptic vesicles. Our findings suggest that PCLO is crucial for the development and survival of a wide range of neuronal types in the human brain. Neurology ® 2015;84:1745-1750 GLOSSARY dbSNP 5 Single Nucleotide Polymorphism Database; ExAC 5 Exome Aggregation Consortium; FPKM 5 fragments per kilobase of exon per million fragments mapped; GATK 5 Genome Analysis Toolkit; indel 5 insertion-deletion; LOD 5 logarithm of odds; NHLBI 5 National Heart, Lung, and Blood Institute; PCH 5 pontocerebellar hypoplasia; PCH3 5 pontocerebellar hypoplasia type III.

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Section: Resultsmentioning

confidence: 99%

Loss of PCLO function underlies pontocerebellar hypoplasia type III

et al. 2015

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“…Each animal underwent up to 5 recording sessions, each lasting about 1 h and performed at least 1 wk apart. A detailed description of the procedure for ERG measurements in mice can be found elsewhere Regus-Leidig et al 2013. Briefly, the animals were dark-adapted overnight, and all further handling was performed under deep red illumination.…”

Section: Methodsmentioning

confidence: 99%

Rod- and cone-driven responses in mice expressing human L-cone pigment

Tsai

Atorf

Neitz

et al. 2015

Journal of Neurophysiology

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Tsai TI, Atorf J, Neitz M, Neitz J, Kremers J. Rod-and cone-driven responses in mice expressing human L-cone pigment. J Neurophysiol 114: 2230 -2241, 2015. First published August 5, 2015 doi:10.1152/jn.00188.2015.-The mouse is commonly used for studying retinal processing, primarily because it is amenable to genetic manipulation. To accurately study photoreceptor driven signals in the healthy and diseased retina, it is of great importance to isolate the responses of single photoreceptor types. This is not easily achieved in mice because of the strong overlap of rod and M-cone absorption spectra (i.e., maxima at 498 and 508 nm, respectively). With a newly developed mouse model (Opn1lw LIAIS ) expressing a variant of the human L-cone pigment (561 nm) instead of the mouse M-opsin, the absorption spectra are substantially separated, allowing retinal physiology to be studied using silent substitution stimuli. Unlike conventional chromatic isolation methods, this spectral compensation approach can isolate single photoreceptor subtypes without changing the retinal adaptation. We measured flicker electroretinograms in these mutants under ketamine-xylazine sedation with double silent substitution (silent S-cone and either rod or M/L-cones) and obtained robust responses for both rods and (L-)cones. Small signals were yielded in wild-type mice, whereas heterozygotes exhibited responses that were generally intermediate to both. Fundamental response amplitudes and phase behaviors (as a function of temporal frequency) in all genotypes were largely similar. Surprisingly, isolated (L-)cone and rod response properties in the mutant strain were alike. Thus the LIAIS mouse warrants a more comprehensive in vivo assessment of photoreceptor subtype-specific physiology, because it overcomes the hindrance of overlapping spectral sensitivities present in the normal mouse. keywords electrophysiology; mouse; photoreceptors; silent substitution IN RECENT YEARS, THE MOUSE has been the mainstay model for studying the physiology of the retina and retinal diseases. In vivo studies of retinal electrophysiology can be achieved by electroretinography (ERG). This method is noninvasive and enables repeated measurements from the same animal. Recent developments in ERG recordings in humans have shown that ERGs not have only a clinical value but also may give information on information processing in major retinogeniculate pathways with relevance for basic visual neuroscience (Kremers and Link 2008;Kremers et al. 2010;Parry et al. 2012). This relevance was recently confirmed for the mouse (Allen et al. 2014). To be able to study retinal signal processing and its disease-related changes, it is of great importance to isolate the responses of single photoreceptor types and record the signals that each elicits downstream. Also, in other studies of the retinal physiology, isolation of photoreceptor responses may lead to a better understanding of the information processing in the retina and for associated visual functions (Brown et al. 2010(Brown et al. , 2...

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“…Other known targets of CaMKII, such as the vesicle-associated proteins PICK-1, synaptophysin, synaptobrevin, synaptotagmin, and membrane-associated syntaxin (Benfenati et al, 1992;Rubenstein et al, 1993;Nielander et al, 1995;Hilfiker et al, 1999a, b;Risinger and Bennett, 1999;Verona et al, 2000;Kim et al, 2002;Ohyama et al, 2002), might also underlie the effects of vesicle replenishment in cones. CaMKII might also act to phosphorylate other ribbon-specific proteins, such as RIBEYE or piccolino (Regus-Leidig et al, 2013), to regulate vesicle attachment probability.…”

Section: Potential Molecular Mechanisms Of Ca 2+ /Cam Effectsmentioning

confidence: 99%

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

Hook¹,

Parmelee²,

Chen³

et al. 2014

J Cell Biol

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At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca 2+ ) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant,  = 1/(Ds), where D is the vesicle diffusion coefficient,  is the vesicle diameter,  is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higherfrequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons.

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Identification and Immunocytochemical Characterization of Piccolino, a Novel Piccolo Splice Variant Selectively Expressed at Sensory Ribbon Synapses of the Eye and Ear

Cited by 65 publications

References 37 publications

Loss of PCLO function underlies pontocerebellar hypoplasia type III

Loss of PCLO function underlies pontocerebellar hypoplasia type III

Rod- and cone-driven responses in mice expressing human L-cone pigment

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

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