Biology subjects

Zoidl, C.

Publications and source records attributed to Zoidl, C..

4 recordsLinked to original sources

bioRxiv2024

Pannexin-2 deficient zebrafish develop ocular and visual motor behaviour defects

Pannexin-2 (Panx2) is a unique ion channel localized to ER-mitochondria contact sites. These dynamic and specialized microdomains are abundant in neurons and glia and essential for cellular signaling and metabolism. While synaptic interactions are well-studied, the role of intracellular contacts, such as those of ER-mitochondrial junctions, in neuronal function and neurodegeneration remains largely unexplored. To investigate the roles of Panx2 in neuronal communication, we meticulously examined its expression pattern in the zebrafish brain and used TALEN technology to generate homozygous Panx2 knockout (Panx2{Delta}11) zebrafish. Our results demonstrate that panx2 mRNA is present in several brain regions, notably in visual centers such as the optic tectum and the thalamus. In 6 days post fertilization TL (Panx2+/+) larvae, Panx2 expression was observed in the inner and outer plexiform layers of the retina and the arborization fields of the optic tract. Transcriptome profiling of Panx2{Delta}11 larvae by RNA-seq analysis revealed down-regulation of vision-related genes, specifically those involved in visual and sensory perception and lens development. Behavioral tests showed that loss of Panx2 leads to an altered ability to interpret visual information, such as changes in ambient illuminations, and respond with the characteristic motor action. Panx2{Delta}11 larvae exhibited reduced locomotor activity during light and increased activity during dark phases. Additionally, the knockout larvae displayed significantly impaired optomotor response (OMR). Lastly, when we tested the retinal structure of adult zebrafish eyes using optical coherence tomography (OCT), Panx2{Delta}11 fish revealed a longer mean axial length and a negative shift in retinal refractive error (RRE) values; both indicative of myopia. Our findings highlight a distinct, novel function of Panx2 in retinal development, visual perception, and ocular health, beyond its recognized roles in neurodevelopment and tumor-suppressing properties in cancer cells.

neuroscience↗

bioRxiv2024

Panx1 deletion promotes synaptic reconfiguration and recruitment of cell death pathways in the Zebrafish MPTP model

Pannexin-1 channels have garnered attention for their implications in neurodevelopment, potentially having a dual role in mediating a delicate balance between cell death and survival. However, a comprehensive understanding of the underlying molecular and cellular mechanisms and Panx1s potential protective functions throughout neurodevelopment remains to be determined. Zebrafish larvae with loss of Pannexin-1a function were subjected to an acute exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Early-life changes in larvae induced by uncoupling of oxidative phosphorylation were investigated by a computational Gene Set Expression Analysis of RNA-seq data and experimental testing of light-stimulated locomotor behavior, cell death, and bioelectrical properties of local field potentials in the ascending visual pathway. A KEGG pathway analysis underscored Panx1as regulatory influence on neurodevelopment. Targeting Panx1a caused a deregulation of oxidative phosphorylation, glycolysis, reactive oxygen production, hypoxia, unfolded protein response pathways, and reduced extracellular ATP. Further, Panx1a ablation enhanced the transcriptional activation of 5 AMP-activated protein kinase (AMPK) kinase, a cellular energy sensor activated by falling energy status, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. The activation of the AMPK pathway in Panx1a knock-out larvae correlated with the stimulation of the mammalian target of rapamycin (mTORC1) pathway that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain cellular homeostasis. The differential expression of mTORC1 pathway genes associated with autophagy, and apoptosis signaling pathways. The resultant cell death was pronounced in the pallium and tectum regions. The loss of cells interrelated with a trans-synaptic a loss of synaptic neurotransmitter receptor and ion channel/transporter expression. Local field potential recordings in the optic tectum and pallium demonstrated that Panx1as involvement in modulating local neuronal networks was altered. Collectively, the results shed light on the impacts of acute MPTP treatment on locomotor behavior, transcriptomic shifts, metabolic disturbances, and the pivotal role of Panx1a in cell death. These insights enhance our comprehension of the intricate molecular and cellular mechanisms underpinning neurodevelopment, with implications for potential therapeutic strategies targeting Panx1 channels in autism and Alzheimers disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/590821v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1a8688eorg.highwire.dtl.DTLVardef@16849a3org.highwire.dtl.DTLVardef@1ba8298org.highwire.dtl.DTLVardef@1d3efff_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA genetic model was combined with the neurotoxin MPTP to explore the roles of zebrafish Pannexin-1 channels in neurodevelopment under oxidative stress conditions. C_LIO_LIA potential beneficial impact of targeting Panx1a is superseded by synaptic plasticity loss, dysfunctional mitochondrial metabolism, and cell death pathway activation. C_LIO_LILoss of Panx1a amplifies AMPK/mTORC1 pathway activation of cell death pathways. C_LIO_LIA role of Panx1a as a regulator of energy and synaptic homeostasis was identified. C_LI

neuroscience↗

bioRxiv2021

Panx1b modulates the luminance response and direction of motion in the zebrafish

Pannexin1 (Panx1) can form ATP-permeable integral membrane channels that play roles in the physiology of the visual system. Two independent gene copies of Panx1, panx1a and panx1b, have been identified in the zebrafish with unique and shared properties and tissue expression patterns. Panx1a channels, located in horizontal cells of the outer retina, modulate light decrement detection through an ATP/pH-dependent mechanisms and adenosine/dopamine signaling. Here, we decipher how the strategic localization of Panx1b channels in the inner retina and ganglion cell layer modulates visually evoked motor behavior. We describe a panx1b knockout model generated by TALEN technology. The RNA-seq analysis of 6 days post-fertilization larvae is confirmed by Real-Time PCR and paired with testing of visual-motor behaviors. The Panx1b protein emerges as a modulator of the circadian clock system. The loss of panx1b also disrupts the retinal response to the abrupt loss of illumination and decreases the larval ability to follow leftward direction of motion in the dark. The evidence suggests that in the retina Panx1b contributes to the OFF pathways function, like Panx1a, though through different signaling mechanisms. In this process, the loss of Panx1b channels compromises the final output of luminance as well as direction of motion detector RGCs. In addition, the disruption of the circadian clock system in mutants suggests that Panx1b could participate in non-image forming processes in the inner retina.

neuroscience↗

bioRxiv2021

Panx1 channels promote both anti- and pro-seizure-like activities in the zebrafish via p2rx7 receptors and ATP signaling

The molecular mechanisms of excitation-inhibition imbalances promoting seizure generation in epilepsy patients are not fully understood. Experimental evidence suggests that Pannexin1 (Panx1), an ATP release channel, modulates excitability of the brain. In this report, we have performed behavioral and molecular phenotyping experiments on zebrafish larvae bearing genetic or pharmacological knockouts of panx1a or panx1b channels, each highly homologous to human PANX1. When Panx1a function is lost or both channels are under pharmacological blockage, treatment with pentylenetetrazol to induce seizures causes reduced ictal-like events and seizure-like locomotion. These observations were extended by transcriptome profiling, where a spectrum of distinct metabolic and cell signaling states correlates with the loss of panx1a. The pro- and anticonvulsant activities of both Panx1 channels affects ATP release and involves the purinergic receptor p2rx7. We propose that Panx1 zebrafish models offer opportunities to explore the molecular and physiological basis of seizures and assist anticonvulsant drug discovery.

neuroscience↗