Tulp3 deficiency results in ciliopathy phenotypes during zebrafish embryogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1279078 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Ciliopathies, caused by defective cilia biogenesis or function, comprise a genetically and clinically diverse group of diseases. Primary cilia play pivotal roles in the regulation of a multitude of signalling pathways during development and tissue homeostasis. Cilia assembly, maintenance and signalling depend on the intraflagellar transport (IFT). Tubby-like protein 3 (TULP3) functions as an adapter protein for the ciliary trafficking of diverse membrane cargos via an interaction with the IFT-A complex. Recently, we and others have shown that individuals carrying pathogenic TULP3 variants suffer from progressive liver, kidney and heart disease. In line with these findings, adult Tulp3 knockout zebrafish displayed liver fibrosis and kidney cyst phenotypes. In the present study, we analysed the functional consequences of Tulp3 deficiency during zebrafish embryogenesis. Tulp3 deficiency resulted in well-known ciliopathy-associated phenotypes including pronephric cysts, otolith deposition defects, body curvature and altered left-right asymmetry. Our analysis of urotensin 2-related peptide (Urp) signaling, which is required for proper spine morphogenesis, revealed reduced expression of urp1 in Tulp3 knockout embryos. We also observed severe scoliosis in a significant number of adult Tulp3 knockout zebrafish. Analysis of ciliogenesis revealed a reduced cilia number and ciliary length in Tulp3 deficient embryos. In addition, Tulp3 deficiency resulted in upregulation of cilia-dependent profibrotic Wnt and Jak/Stat signalling components. Furthermore, we demonstrate that loss of Tulp3 causes upregulation of genes related to liver fibrosis. In conclusion, our data highlights a critical role of Tulp3 in proper cilia formation and function to maintain healthy tissue architecture during zebrafish embryogenesis, and provides further insight into the spectrum of cilia-related phenotypes in adult zebrafish depleted for Tulp3 functions.
2025-09-01 | GSE300126 | GEO
Project description: Not available
| S-EPMC12432116 | biostudies-literature
Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
2023-04-26 | GSE230552 | GEO
Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
2022-07-28 | GSE209661 | GEO
Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
2022-07-28 | GSE209660 | GEO
Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
2022-07-28 | GSE209659 | GEO
Project description:Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.
2016-08-15 | PXD004741 | Pride
Project description:Ciliopathies are a family of disorders involving mutations in over 150 genes affecting the primary cilium, with retinal degeneration as a prominent feature driven by concomitant developmental and maturation defects in photoreceptors and the retinal pigment epithelium (RPE). Current single-gene-targeted therapeutic approaches are expensive with limited scalability. We hypothesized that downstream of primary cilium dysfunction, mutation-agnostic shared pathways initiate tissue defects. To test this hypothesis, we developed induced pluripotent stem cell-derived RPE models (iRPE) from multiple (BBS1, BBS10, BBS16, CEP290, LCA5, MYO7A, PRPF31) ciliopathy patients with severe retinal degeneration. Despite varying in severity, consistent with the structural ciliary defects, all ciliopathy iRPE displayed abnormal epithelial polarization and mitochondrial health initiated by dysregulated TGF-B signaling driven mesenchymal drift. Addressing these gene-agnostic disease phenotypes, our study identifies two drugs, Pioglitazone, a mitochondrial metabolic modulator, and Galunisertib, a TGFBR1 inhibitor, as potential therapeutic candidates for multiple ciliopathy subtypes.
2026-07-30 | GSE316614 | GEO
Project description:Xist Deletion in B Cells Results in Systemic Lupus Erythematosus Phenotypes
| PRJNA1368924 | ENA
Project description:Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein resulting from mutations in the SMN1 gene. Several therapeutic approaches capable of boosting SMN are now approved for use in human patients, delivering remarkable improvements in lifespan and symptom severity. However, new and unexpected phenotypes are being reported in treated SMA patients, including growing evidence for significant neurodevelopmental comorbidities in some individuals, indicative of alterations in brain development. Here, using a mouse model of severe SMA, we reveal an underlying neurodevelopmental phenotype in SMA where prenatal SMN-dependent defects in translation drive a primary ciliopathy in the CNS. Cell proliferation was significantly reduced in the hippocampus of SMA mice at E14.5, accompanied by widespread perturbations in translation, disrupting genes associated with primary cilia. The density of primary cilia in vivo, as well as cilial length in vitro, was significantly decreased in prenatal SMA mice, revealing core morphological hallmarks of a primary ciliopathy. Prenatal transplacental therapeutic intervention with an SMN-restoring small molecule (Risdiplam) rescued primary cilia defects in SMA mouse embryos. We conclude that SMN protein is required for normal cellular and molecular development of the CNS, with low levels in SMA driving a primary ciliopathy. Early, systemic treatment with SMN-restoring therapies is likely to be required to target neurodevelopmental comorbidities.
2025-09-01 | GSE295681 | GEO