The neuronal cilium – a highly diverse and dynamic organelle involved in sensory detection and neuromodulation

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(5), P. 383 - 394

Published: April 4, 2024

Cilia are fascinating organelles that act as cellular antennae, sensing the environment. gained significant attention in late 1990s after their dysfunction was linked to genetic diseases known ciliopathies. Since then, several breakthrough discoveries have uncovered mechanisms underlying cilia biogenesis and function. Like most cells animal kingdom, neurons also harbor cilia, which enriched neuromodulatory receptors. Yet, how neuronal modulate physiology behavior remains poorly understood. By comparing ciliary biology between sensory central nervous systems (CNS), we provide new perspectives on functions of brain physiology.

Language: Английский

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Ultrastructural differences impact cilia shape and external exposure across cell classes in the visual cortex

Current Biology, Journal Year: 2024, Volume and Issue: 34(11), P. 2418 - 2433.e4

Published: May 14, 2024

A primary cilium is a membrane-bound extension from the cell surface that contains receptors for perceiving and transmitting signals modulate state activity. Primary cilia in brain are less accessible than on cultured cells or epithelial tissues because they protrude into deep, dense network of glial neuronal processes. Here, we investigated frequency, internal structure, shape, position large, high-resolution transmission electron microscopy volumes mouse visual cortex. Cilia extended bodies nearly all excitatory inhibitory neurons, astrocytes, oligodendrocyte precursor (OPCs) but were absent oligodendrocytes microglia. Ultrastructural comparisons revealed base microtubule organization differed between neurons glia. Investigating cilia-proximal features many directly adjacent to synapses, suggesting poised encounter locally released signaling molecules. Our analysis indicated synapse proximity likely due random encounters neuropil, with no evidence activity as would be expected tetrapartite synapses. The observed class differences synapses largely external length. Many key structural influenced both placement shape and, thus, exposure processes outside cilium. Together, ultrastructure within around suggest formation function across types brain.

Language: Английский

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Nanometer-scale views of visual cortex reveal anatomical features of primary cilia poised to detect synaptic spillover

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 1, 2023

A primary cilium is a thin membrane-bound extension off cell surface that contains receptors for perceiving and transmitting signals modulate state activity. While many types have cilium, little known about cilia in the brain, where they are less accessible than on cultured cells or epithelial tissues protrude from bodies into deep, dense network of glial neuronal processes. Here, we investigated frequency, internal structure, shape, position large, high-resolution transmission electron microscopy volumes mouse visual cortex. Cilia extended nearly all excitatory inhibitory neurons, astrocytes, oligodendrocyte precursor (OPCs), but were absent oligodendrocytes microglia. Structural comparisons revealed membrane structure at base microtubule organization differed between neurons glia. OPC distinct shortest contained pervasive vesicles only occasionally observed neuron astrocyte cilia. Investigating cilia-proximal features directly adjacent to synapses, suggesting well poised encounter locally released signaling molecules. proximity synapses was random, not enriched, synapse-rich neuropil. The anatomy, including changes centriole location, defined key structural placement shape. Together, anatomical insights both within around glia provide new formation function across brain.

Language: Английский

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The Primary Cilia are Associated with the Axon Initial Segment in Neurons

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract The primary cilia serve as pivotal mediators of environmental signals and play crucial roles in neuronal responses. Disruption ciliary function has been implicated circuit disorders aberrant excitability. However, the precise mechanisms remain elusive. To study link between excitability, manipulation somatostatin receptor 3 (SSTR3) is investigated, an example how alterations signaling may affect activity. It found that SSTR3 expression perturbed not only morphology but also disrupted cascades. Genetic deletion resulted spatial memory synaptic plasticity. axon initial segment (AIS) a specialized region where action potentials are initiated. Interestingly, loss led to decrease Akt‐dependent cyclic AMP‐response element binding protein (CREB)‐mediated transcription at AIS, specifically downregulating AIS master organizer adaptor ankyrin G (AnkG) expression. In addition, other proteins serotonin 6 (5‐HT6R)and intraflagellar transport 88 (IFT88) induced length changes AIS. findings elucidate specific interaction providing insight into impact on excitability integrity.

Language: Английский

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Defining the Polycystin Pharmacophore Through HTS & Computational Biophysics.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Polycystins (PKD2, PKD2L1) are voltage-gated and Ca 2+ -modulated members of the transient receptor potential (TRP) family ion channels. Loss PKD2L1 expression results in seizure-susceptibility autism-like features mice, whereas variants PKD2 cause autosomal dominant polycystic kidney disease. Despite decades evidence clearly linking their dysfunction to human disease demonstrating physiological importance brain kidneys, polycystin pharmacophore remains undefined. Contributing this knowledge gap is resistance drug screening campaigns, which hindered by these channels' unique subcellular trafficking organelles such as primary cilium. only member form constitutively active channels on plasma membrane when overexpressed. HEK293 cells stably expressing F514A were pharmacologically screened via high-throughput electrophysiology identify potent channel modulators. In-silico docking analysis mutagenesis used define sites screen hits. Inhibition membrane-impermeable QX-314 was evaluate PKD2L1's binding site accessibility. Screen antagonists with divergent chemical core structures highlight striking similarities between molecular pharmacology sodium Docking analysis, mutagenesis, recordings an open-state accessible lateral fenestration within pore, a mechanism inhibition that stabilizes inactivated state. Outcomes establish suitability our approach expand polycystins delineates novel moieties for development channel-specific TRP research.

Language: Английский

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The BBS/CCT chaperonin complex ensures the localization of the adhesion G protein-coupled receptor ADGRV1 to the base of primary cilia

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 4, 2025

Primary cilia are antenna-like sensory organelles present on almost all eukaryotic cells. Their capacity relies receptors, in particular G-protein-coupled receptors (GPCRs) which localize to the ciliary membrane. Here we show that ADGRV1, a member of GPCR subfamily adhesion GPCRs, is part large protein network, interacting with numerous proteins comprehensive proteome. ADGRV1 localized base prototypic primary cultured cells and modified retinal photoreceptors, where it interacts TRiC/CCT chaperonins Bardet Biedl syndrome (BBS) chaperonin-like proteins. Knockdown CCT2 3, BBS6 result common ciliogenesis phenotypes, namely reduced ciliated combined shorter cilia. In addition, localization depends activity co-complex BBS absence components TRiC/CCT-BBS chaperonin co-complex, depleted from cilium degraded via proteasome. Defects may lead an overload proteasomal degradation processes imbalanced proteostasis. Dysfunction or underly pathophysiology human Usher type 2 epilepsy caused by mutations .

Language: Английский

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Methods to Assess Neuronal Primary Cilia Electrochemical Signaling

Journal of Cellular Physiology, Journal Year: 2025, Volume and Issue: 240(4)

Published: April 1, 2025

ABSTRACT Primary cilia are polymodal sensory organelles which project from the apical side of polarized cells. They found in all brain hemispheres but most pronounced neurons, comprise granular layers hippocampus and cerebellum. Pathogenic variants genes encode primary components responsible for neuronal ciliopathies—a group central nervous system disorders characterized by neurodevelopmental conditions such as intellectual disability, seizure, ataxia, deficits. In hippocampus, form chemical synapses with axons their membranes populated unique sets ion channels G protein‐coupled receptors (GPCRs). small privileged compartments that challenging to study. detail, we describe electrophysiology methods use cilia‐specific fluorescent sensors assay polycystin channel function serotonergic receptor signaling, respectively. These tools allow researchers calcium, cAMP channel‐related signaling pathways isolated neurons real‐time semi‐quantitative terms, while enhancing our understanding this understudied organelle its dysregulation ciliopathy disease states.

Language: Английский

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Pkd2l1 deletion inhibits the neurogenesis of cerebrospinal fluid-contacting neurons and impedes spinal cord injury repair

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: April 23, 2025

Language: Английский

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A synthetic method to assay polycystin channel biophysics

eLife, Journal Year: 2024, Volume and Issue: 13

Published: July 10, 2024

Ion channels are biological transistors that control ionic flux across cell membranes to regulate electrical transmission and signal transduction. They found in all their conductive state kinetics frequently disrupted human diseases. Organelle ion among the most resistant functional pharmacological interrogation. Traditional channel protein reconstitution methods rely upon exogenous expression and/or purification from endogenous cellular sources which contaminated by resident ionophores. Here, we describe a fully synthetic method assay properties of polycystin natively traffic primary cilia endoplasmic reticulum organelles. Using this method, characterize oligomeric assembly, membrane integration, orientation, conductance while comparing these results properties. Outcomes define novel approach can be applied broadly investigate biophysical analysis characterization.

Language: Английский

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Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 15, 2024

Abstract Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity >40 causative genes that encode proteins localising to the primary cilium, sensory organelle essential for transduction of signalling pathways during neurodevelopment, among other vital functions. localise distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there no unifying pathomechanism explain how dysfunction such cilia-related results brain abnormality. In order identify shared consequence gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants JBTS-causative cc2d2a uw38 , cep290 fh297 inpp5e zh506 talpid3 i264 and togaram1 zh510 Bardet-Biedl syndrome-causative bbs1 k742 . We identified commonly dysregulated these yet all displayed an enrichment altered sets related central nervous system function. found have cilia throughout brain, however do not display abnormal morphology. Nonetheless, behavioural analyses revealed reduced locomotion loss postural control which, together results, hint at underlying abnormalities neuronal activity and/or circuit These models therefore offer unique opportunity study role function beyond early patterning, proliferation differentiation. Summary Statement leads cilia, transcription neuron-associated swimming behaviour despite normal

Language: Английский

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