Ciliogenesis defects after neurulation impact brain development and neuronal activity in larval zebrafish
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1021586 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Cilia are slender, hair-like structures extending from cell surfaces and playing essential roles in diverse physiological processes. Within the nervous system, primary cilia contribute to signaling and sensory perception, while motile cilia facilitate cerebrospinal fluid flow. Here, we investigated the impact of ciliary loss on neural circuit development using a zebrafish line displaying ciliogenesis defects. We found that cilia defects after neurulation affects neurogenesis and brain morphology, especially in the cerebellum, and lead to altered gene expression profiles. Using whole brain calcium imaging, we measured reduced light-evoked and spontaneous neuronal activity in all brain regions. By shedding light on the intricate role of cilia in neural circuit formation and function in the zebrafish, our work highlights their evolutionary conserved role in the brain and set the stage for future analysis of ciliopathy models.
2024-04-16 | GSE244171 | GEO
Project description:Engrailed 1 deficiency induces changes in ciliogenesis during human neuronal differentiation
| PRJNA1023165 | ENA
Project description:A key pathological feature of Parkinson's Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn't interfere with neuronal differentiation and generation of tyrosine hydroxylase positive (TH+) neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.
2024-03-12 | GSE244435 | GEO
Project description:Wild-type or miR-302 knockout tissue was isolated from embryos during neurulation in replicate
2015-08-03 | GSE62396 | GEO
Project description:Neuronal Defects in a Human Cellular Model of 22q11.2 Deletion Syndrome
| PRJNA606070 | ENA
Project description:Dysfunction of cell cycle control and defects of primary ciliogenesis are two features of many cancers. Whether these events are interconnected and the driving mechanism controlling and coordinating these events remains largely unknown. Here we identified an actin branching surveillance system that alerts cells for the insufficiency of the actin branching network controlling the restriction point, cytokinesis， and primary ciliogenesis. We found that the ciliopathy protein Oral-Facial-Digital syndrome 1 (OFD1) functions as a previously undescribed class II NPF to promote Arp2/3 complex-mediated actin branching synergistically with class I NPF via its C-terminal acidic domain. Perturbation of actin branching promotes OFD1 degradation and inactivation via a liquid-to-gel transition at centriolar satellites. Elimination of OFD1 or disruption of OFD1-Arp2/3 interaction promotes ciliogenesis and drives proliferating, non-transformed cells into quiescence by an RB-dependent mechanism that is independent of ciliogenesis, senescence, or centrosome loss, which could be reversed by oncogene overactivation. Oncogene-transformed cells, as well as most cancer cells, bypass the G1/S checkpoint in the absence of OFD1 but fail to assemble actin filaments on the actomyosin ring, resulting in incomplete cytokinesis and irreversible mitotic catastrophe. Inhibition of OFD1 leads to marked suppression of pancreatic, colon, and triple-negative breast cancer cell growth in mouse xenograft models. Thus, cancer cells display a major difference from normal cells in their response to the OFD1-mediated actin branching surveillance system, and targeting this surveillance system provides a new direction for cancer therapy.
2023-02-15 | GSE225003 | GEO
Project description:Multiple FTD patient-specific iPSC lines were generated for the first time, Human neurons of progranulin haploinsufficiency have been established. PGRN S116X neurons are more sensitive to kinase inhibitors-induced cell stress, which can be rescued by ectopic progranulin expression, revealing progranulin-dependent cellular defects in FTD. Microarray analysis reveals that the serine/threonine kinase S6K2 (RPS6KB2) and other genes involved in MAPK signaling are dysregulated specifically in neurons with progranulin deficiency. 32 independent human neuronal cultures were analyzed in this study
2012-10-25 | E-GEOD-40378 | biostudies-arrayexpress
Project description:Wild-type or miR-302 knockout tissue was isolated from embryos during neurulation in replicate Performed in biological triplicate except for E7.5 WT which was in duplicate and E9.5 timepoints which were in quadruplicate. Biological replicate samples represent independent embryos. Total RNA collected with Trizol. All processing conducted at the UCLA Neuroscience Genomics Core. MouseRef-8 v2.0 Expression BeadChips.
2015-08-03 | E-GEOD-62396 | biostudies-arrayexpress
Project description:Adenosine N6-methylation (m6A) is one of the most pervasive mRNA modifications, and yet the physiological significance of m6A removal (demethylation) remains elusive. Here we report the m6A demethylase FTO functions as a conserved regulator of motile ciliogenesis. Mechanistically, FTO demethylates and thereby stabilizes the mRNA encoding the master ciliary transcription factor FOXJ1. Depletion of Fto in Xenopus laevis embryos caused widespread motile cilia defects, and Foxj1 was identified as one of the major phenocritical targets. In primary human airway epithelium, FTO depletion also led to FOXJ1 mRNA destabilization and a severe loss of ciliated cells with an increase of neighboring goblet cells. Consistently, Fto knockout mice showed strong asthma-like phenotypes upon allergen challenge owing to defective ciliated cells in the airway epithelium. Altogether, our study reveals a conserved role of the FTO-FOXJ1 axis in embryonic and homeostatic motile ciliogenesis.
2021-02-20 | GSE167139 | GEO
Project description:Actomyosin contractility represents an ancient feature of eukaryotic cells participating in many developmental and homeostasis events, including tissue morphogenesis, muscle contraction, and cell migration, with dysregulation implicated in various pathological conditions, such as cancer. At the molecular level, actomyosin comprises actin bundles and myosin motor proteins that are sensitive to posttranslational modifications like phosphorylation. While the molecular components of actomyosin and its regulation are well understood, the coordination of contractility by extracellular and intracellular signals, particularly from cellular signaling pathways, remains incompletely elucidated. This study focuses on planar cell polarity (PCP) signaling, previously associated with actomyosin contractility during vertebrate neurulation. Contrary to previous studies, our investigation reveals that main cytoplasmic PCP proteins, Prickle and Dishevelled, interact directly with key actomyosin components such as myosin light chain (MLC), leading to its phosphorylation and localized activation. Through relevant in vitro and in vivo models, we demonstrate that these PCP proteins function not merely passively and indirectly as previously reported, but that they actively control actomyosin contractility by acting as scaffold proteins, orchestrating the necessary machinery for contractility. These findings unveil a direct link of PCP signaling in crucial actomyosin contractility processes through MLC that are relevant to vertebrate neurulation and potentially beyond.
2024-09-19 | PXD052350 | Pride