Shroom3 Affects Neuroepithelial Morphogenesis through Regulating Cytoskeletal Proteins in Cynomolgus Monkey’s Organoids
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ABSTRACT:
ORGANISM(S): Macaca fascicularis
PROVIDER: GSE217791 | GEO | 2025/11/01
REPOSITORIES: GEO
Similar Datasets
Project description:Shroom3 Affects Neuroepithelial Morphogenesis through Regulating Cytoskeletal Proteins in Cynomolgus Monkey’s Organoids
| PRJNA900552 | ENA
Project description:Neural tube defects (NTDs) including anencephaly and spina bifida are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or life-long severe complications (spina bifida). Despite hundreds of genetic mouse models having neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals such as antiseizure medications have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette spheroid (SOSRS) brain organoid system, we have developed a high-throughput image analysis pipeline for evaluating SOSRS structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. This expansion was mimicked by GSK3b and HDAC inhibitors; however, RNA sequencing suggests VPA does not inhibit GSK3b at these concentrations. Knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.
2023-07-19 | GSE232218 | GEO
Project description:Neural tube defects (NTDs) are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure. Although folate supplementation has been shown to mitigate the incidence of NTDs, some cases, often attributable to genetic factors, remain unpreventable. The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation; at present, however, the underlying mechanism remains unclear. Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate. To determine the role of SHROOM3 in early developmental morphogenesis, we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase. Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei. These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins, namely fibrous actin (F-actin), myosin II, and phospho-myosin light chain (PMLC), to the apical side of the neuroepithelial cells. Notably, these defects were not rescued by folate supplementation. RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis. In summary, we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.
| S-EPMC11017078 | biostudies-literature
Project description:Individual cell shape and integrity must precisely be orchestrated during morphogenesis. Here, we determine function of type II cadherins, Cdh6, Cdh8, and Cdh11, whose expression combinatorially demarcates the mouse neural plate/tube. While CRISPR/Cas9-based single type II cadherin mutants show no obvious phenotype, Cdh6/8 double knockout mice develop intermingled forebrain/midbrain compartments as these two cadherins’ expression opposes at the nascent boundary. Cdh6/8/11 triple, Cdh6/8 double or Cdh8/11 double knockout mice further cause exencephaly just within the cranial region where mutated cadherins’ expression merges. In the Cdh8/11 double knockout midbrain, we observe less-constricted apical actin meshwork, ventrally-directed spreading, and occasional hyperproliferation among dorsal neuroepithelial cells as origins for exencephaly. These results provide rigid evidence that, by conferring distinct adhesive codes to each cell, redundant type II cadherins serve essential and shared roles in compartmentalization and neurulation, both of which proceed under the robust control of the number, positioning, constriction, and fluidity of neuroepithelial cells.
2020-09-16 | GSE157008 | GEO
Project description:Animal organs exhibit complex topologies involving cavities and tubular networks, which underlie their form and function1-3. However, how topology emerges during the development of organ shape, or morphogenesis, remains elusive. Here we combine tissue reconstitution and quantitative microscopy to show that tissue topology and shape is governed by two distinct modes of topological transitions4,5. One mode involves the fusion of two separate epithelia and the other involves the fusion of two ends of the same epithelium. The morphological space is captured by a single control parameter that can be traced back to the relative rates of the two epithelial fusion modes. Finally, we identify a pharmacologically accessible pathway that regulates the frequency of two modes of epithelial fusion, and demonstrate the control of organoid topology and shape. The physical principles uncovered here provide fundamental insights into the self-organization of complex tissues6.
| S-EPMC9928582 | biostudies-literature
Project description:Developing a model of primate neural tube (NT) development is important to promote many NT disorder studies in model organisms. Here, we report a robust and stable system to allow for clonal expansion of single monkey neuroepithelial stem cells (NESCs) to develop into miniature NT-like structures. Single NESCs can produce functional neurons in vitro, survive and extensively regenerate neuron axons in monkey brain. NT formation and NESC maintenance depend on high metabolism activity and Wnt signaling. NESCs are regionally restricted into a telencephalic fate. Moreover, single NESCs can turn into radial glial progenitors (RGPCs). The transition is accurately regulated by Wnt signaling through regulation of Notch signaling and adhesion molecules. Finally, using the â??NESC-TO-NTsâ?? system, we model the functions of folic acid (FA) on NT closure and demonstrate FA can regulate multiple mechanisms to prevent NT defects. Together, our system is ideal for studying NT development and diseases. compare gene expression profiles in monkey neuroepithelial stem cells (NESCs), newly converted radial glial progenitor cells (RPGCs) from NESCs and differentiated neurons from NESCs
2015-11-21 | E-GEOD-73892 | biostudies-arrayexpress
Project description:Background: Although adequate periconceptional folic acid (FA) supplementation has reduced the occurrence of neural tube defects (NTDs)-affected pregnancies, mechanisms underlie FA resistant NTDs are poorly understood, so that NTDs still remain a global public health concern now. It has been proven that high level of Krüppel-like factor 12 (KLF12) has bad effects on heath in most cases, but there is no evidence concerning its roles during development. Methods: We used KLF12-overexpression mice to study the effects of high level of KLF12 on neural tube development. Findings: We showed KLF12-overexpression fetuses died in utero at around 10.5 days post coitus with 100% cranial NTDs. Neither FA or formate benefited normal neural tube closure in mutant fetuses. Further anylasis revealed high level of KLF12 caused NTDs in mice via overactivating Sonic hedgehog (Shh) signaling pathway, leading to upregulation of Ptch1, Gli1, Hhip etc. PF-5274857, an antagonist of Shh signaling pathway could significantly promote dorsolateral hinge point formation and partially rescue the phynotype. Interpretation: The regulatory hierarchy between high level of KLF12 and FA-resistant NTDs might provide new insights for the diagnosis and treatment of unexplained NTDs in the future.
2021-02-04 | GSE166054 | GEO
Project description:Background: In the early stage of embryonic development, the neural tube (NT) cannot be closed properly due to some complex factors such as, environmental factors, genetic factors and the relationship between various factors, leading to the occurrence of neural tube defects (NTDs). Methods: In this study, we induced the mouse model of NTDs by feeding mice a low-folate diet and injecting 1.5mg/kg methotrexate on E7.5. Fetal mice were achieved at E13.5, then we extracted proteins from brain tissue with trypsin digestion. After enzymatic digestion, peptides were labeled with TMT/iTRAQ and then separated in high-performance liquid chromatography (HPLC) for subsequent LC-MS/MS analysis. To analyze the functional enrichment of differentially expressed proteins(DEPs) in the NTDs mice tissues with low folate induction, we used Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway annotation to analyze proteomic changes. Results: Low folate induced mouse model was successfully constructed. Folate was used as a sensitizing agent, the teratogenicity rate of the NTDs fetal mice was increased to 36.5% when methotrexate was injected to maternal mice at E7.5. 6614 proteins were identified by mass spectrometry, among them, 5656 proteins were quantified. In the following proteomic analysis, GO classification and KEGG pathway enrichment analysis were conducted, and heatmaps were drawn for differentially expressed proteins(DEPs). Moreover, the main pathways associated with NTDs, such as Hedgehog, Wnt, p53, Hippo signaling pathways, and one carbon pool by folate, can be identified through the generation of a protein-protein interaction (PPI) network. It was also found that the regulation of ribosomal proteins has a certain impact on neural tube development, such as RPL13 and RPL14, which are upregulated in NTDs. Conclusions: Our results revealed proteomic changes in the tissues of low folate induced NTDs mice, as well as validation showed that ribosomal proteins play a regulatory role during the development of NTDs, it provides new ideas for the pathogenesis and preventive measures of NTDs.
2024-03-12 | PXD045752 | Pride
Project description:Genome-wide DNA methylation profiling of 8 low-grade neuroepithelial tumors (LGNET) with FGFR2 fusions with various histologic diagnoses including ganglioglioma, multinodular and vacuolating neuronal tumor (MVNT), low-grade glioneuronal tumor NOS, and polymorphous low-grade neuroepithelial tumor of the young (PLNTY). The Illumina Infinium EPIC 850k Human DNA Methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue of 8 low-grade neuroepithelial tumors with FGFR2 fusions.
2021-07-27 | GSE172081 | GEO
Project description:WDR12 is a ribosome biogenesis factor known to be expressed in Optic tectum Neuroepithelial cells, we define the transcriptome profile of the optic tectum neuroepithelial cells, by cell-sorting followed by RNA-seq (Illumina technology).
2019-04-20 | GSE80497 | GEO