Spatiotemporal dynamics of primary and motile cilia throughout lung development DOI Creative Commons
Stephen B. Spurgin,

Ange Michelle Nguimtsop,

Fatima Chaudhry

et al.

Published: Oct. 26, 2024

Cilia are specialized structures found on a variety of mammalian cells, with variable roles in the transduction mechanical and biological signals (by primary cilia, PC), as well generation fluid flow motile cilia). Their critical role establishment left-right axis early development is described, innate immune function multiciliated upper airway epithelium. By contrast, dynamics ciliary status during organogenesis postnatal largely unknown. In this study, we define progression within endothelium, epithelium, mesenchyme lung. Remarkably, find that endothelial cells (ECs) lack PC at all stages development, except low numbers most proximal portions pulmonary arteries. lung proximodistal gradient established over time, uniformly mono-ciliated epithelium transitions into proximal, distal alveolar loses its cilia. Mesenchymal interestingly, ciliated but restriction to PDGFRα+ fibroblasts adult alveoli. This dynamic process multiple cellular populations both challenges prior assertions highlights need understand their spatiotemporal functions.

Language: Английский

The neuronal cilium – a highly diverse and dynamic organelle involved in sensory detection and neuromodulation DOI Creative Commons
Nathalie Jurisch‐Yaksi, Dagmar Wachten, Jay Gopalakrishnan

et al.

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

Citations

12
Ultrastructural differences impact cilia shape and external exposure across cell classes in the visual cortex DOI Creative Commons
Carolyn Ott, Russel Torres, T. S. Kuan

et al.

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

Citations

8
Postnatal Dynamic Ciliary ARL13B and ADCY3 Localization in the Mouse Brain DOI Creative Commons

Katlyn K. Brewer,

Kathryn M. Brewer, Tiffany T. Terry

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(3), P. 259 - 259

Published: Jan. 30, 2024

Primary cilia are hair-like structures found on nearly all mammalian cell types, including cells in the developing and adult brain. A diverse set of receptors signaling proteins localize within to regulate many physiological developmental pathways, Hedgehog (Hh) pathway. Defects structure, protein localization, function lead genetic disorders called ciliopathies, which present with various clinical features that include several neurodevelopmental phenotypes hyperphagia-associated obesity. Despite their dysfunction being implicated disease states, understanding roles central nervous system (CNS) development has proven challenging. We hypothesize dynamic changes ciliary composition contribute this challenge may reflect unrecognized diversity CNS cilia. The ARL13B ADCY3 established markers is a regulatory GTPase important for regulating trafficking, Hh signaling, adenylyl cyclase. Here, we examine localization perinatal mouse define proportion enriched depending brain region age. Furthermore, identify distinct lengths specific regions male female mice. ARL13B+ become relatively rare age regions, hypothalamic feeding centers, while becomes prominent marker mature It understand endogenous patterns these throughout under different conditions as common be more than initially expected. Understanding regional- developmental-associated signatures condition reveal molecular mechanisms associated commonly observed ciliopathy models like obesity diabetes.

Language: Английский

Citations

5
Phosphorylation at the Helm: Kinase‐Mediated Regulation of Primary Cilia Assembly and Disassembly DOI Creative Commons
Andrea Lacigová, Lukáš Čajánek

Cytoskeleton, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

The primary cilium serves as an antenna of most vertebrate cells and is important for conveying cues from several signaling pathways into appropriate cellular responses during development homeostasis. Cilia assembly disassembly processes are thought to be strictly controlled; however, the precise nature molecular events underlying this control still awaits full resolution. Through their enzymatic activity, kinases function flexible yet highly controllable regulators a vast variety processes. Their activity ranges cell cycle regulation motility, signal transduction, metabolism. This review focuses on emerging role in cilia biology. We underscore functions formation, maintenance, resorption while examining available models respective mechanisms actions.

Language: Английский

Citations

0
Differences in neuronal ciliation rate and ciliary content revealed by systematic imaging-based analysis of hiPSC-derived models across protocols DOI Creative Commons

Walther Haenseler,

Melanie Eschment, Bronwyn A. Evans

et al.

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

Published: April 11, 2025

Introduction Ciliopathies are a group of human Mendelian disorders caused by dysfunction primary cilia, small quasi-ubiquitous sensory organelles. Patients suffering from ciliopathies often display prominent neurodevelopmental phenotypes, underscoring the importance cilia during development and for function central nervous system (CNS). Human tissues, in particular CNS, very hard to obtain research. Patient derived- or genetically engineered induced pluripotent stem cells (hiPSCs) therefore precious resource investigating role neurons. Methods In this study we used variety 2D 3D neuronal differentiation protocols multiple hiPSC lines systematically analyzed ciliation rates ciliary length hiPSCs, neural (NSCs), immature different types mature neurons using immunofluorescence. Results We found that rate varied substantially between cell protocols. Moreover, depended on stage, being maximal NSCs decreasing with maturation. various obtained protocols, be as low ∼10%. Neuronal density also played an important role, higher denser cultures. further investigated protein content these at stages commonly antibodies against ARL13B, INPP5E, AC3 GPR161. Cilia were all positive trend intensity more Likewise, INPP5E was present analyzed, while positivity increased maturation proceeded. Interestingly, GPR161 signal almost completely disappeared upon Sonic hedgehog (SHH) stimulation neurons, not case suggesting possible developmental time window cilia-dependent SHH signaling. Conclusion Taken together, our results provide systematic description hiPSC-derived generated selecting optimal model controls cells.

Language: Английский

Citations

0
FGF overactivation underlies reduced neurogenesis in cerebellar organoid models of neurodevelopmental ciliopathy DOI Creative Commons

Ludovica Brunetti,

Antonia Wiegering,

Isabelle Anselme

et al.

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

Published: April 16, 2025

ABSTRACT A hallmark feature of neurodevelopmental ciliopathies is the hypo-dysplasia cerebellar vermis, as observed among most Joubert Syndrome patients. Despite significant advances in mouse models, pathogenetic mechanisms linking ciliary gene dysfunction to syndrome defects are still poorly understood. In this study, we generated organoids from human induced pluripotent stem cells carrying null mutations or patient-derived variants causal RPGRIP1L , which encodes a scaffold protein crucial for cilia function. Using immunolabelling and transcriptomics, show that WT recapitulate early steps development, including expression markers both Granule Purkinje cell lineages. contrast, derived all -deficient lines exhibit common severe reduction lineage markers, along with decreased neurogenesis. The neurogenesis defect coupled increased progenitor proliferation, well extended overactivation FGF pathway. Restoring normal levels signaling RPGRIP1L- deficient rescues proliferative/neurogenic balance formation. Thus, our results uncover an deregulation hampers correct neuronal differentiation could participate phenotype patients suffering ciliopathies.

Language: Английский

Citations

0
Permanent cilia loss during cerebellar granule cell neurogenesis involves withdrawal of cilia maintenance and centriole capping DOI Creative Commons
Sandii Constable, Carolyn Ott, Andrew L. Lemire

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(52)

Published: Dec. 20, 2024

Brain neurons utilize the primary cilium as a privileged compartment to detect and respond extracellular ligands such Sonic hedgehog (SHH). However, cilia in cerebellar granule cell (GC) disassemble during differentiation through ultrastructurally unique intermediates, process we refer deconstruction. In addition, mature do not reciliate despite having docked centrioles. Here, identify molecular changes that accompany deconstruction centriole docking GC neurons. We used single transcriptomic immunocytological analyses compare transcript levels subcellular localization of proteins between progenitor, differentiating, GCs. Differentiating GCs lacked transcripts for key activators premitotic resorption, indicating disassembly differentiating cells is distinct from resorption. Instead, differentiation, many genes required maintenance—specifically those encoding components intraflagellar transport, pericentrosomal material, centriolar satellites—decreased. The abundance several corresponding around centrosomes also decreased. These coincided with downregulation SHH signaling prior even mutant excessive activation. Finally, mother centrioles maturing recruited cap complex protein, CEP97. data suggest global, developmentally programmed decrease maintenance mediates deconstruction, while capping prevents regrowth dysregulated signaling. Our study provides mechanistic insights expanding our understanding permanent loss multiple tissue-specific contexts.

Language: Английский

Citations

3
Spatiotemporal dynamics of primary and motile cilia throughout lung development DOI Creative Commons
Stephen B. Spurgin,

Ange Michelle Nguimtsop,

Fatima Chaudhry

et al.

Published: Oct. 26, 2024

Cilia are specialized structures found on a variety of mammalian cells, with variable roles in the transduction mechanical and biological signals (by primary cilia, PC), as well generation fluid flow motile cilia). Their critical role establishment left-right axis early development is described, innate immune function multiciliated upper airway epithelium. By contrast, dynamics ciliary status during organogenesis postnatal largely unknown. In this study, we define progression within endothelium, epithelium, mesenchyme lung. Remarkably, find that endothelial cells (ECs) lack PC at all stages development, except low numbers most proximal portions pulmonary arteries. lung proximodistal gradient established over time, uniformly mono-ciliated epithelium transitions into proximal, distal alveolar loses its cilia. Mesenchymal interestingly, ciliated but restriction to PDGFRα+ fibroblasts adult alveoli. This dynamic process multiple cellular populations both challenges prior assertions highlights need understand their spatiotemporal functions.

Language: Английский

Citations

0