Expression data from early and adult stages of mouse development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE11356 | GEO | 2008/05/06
SECONDARY ACCESSION(S): PRJNA106575
REPOSITORIES: GEO
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Project description:DNA repair genes have been shown to be expressed in the early stages of mammalian development probably to reduce possible replication errors and genotoixc damages. Several birth defects and some cancers are due to inappropriate or defective DNA repair machinery indicating that a right activity of DNA repair genes in the early stages of fetal development are essential for an appropriate DNA function. Neuroblastoma (NB), an embryonal tumor deriving from neural crest cells (NCCs) is diagnosed in about 30% of patients within the first year of life. Moreover, several reports show that NB can be detected in foetus and in neonatal period. To assess gene expression profiling of DNA repair genes during early stage of development, we performed a genome-wide analysis of Neural Crest cells (NCCs) generating a gene expression database that can help to better understand the gene(s) involved in both genetic and cancer diseases. We found 11 genes involved in DNA repair activity during mouse embryo development overexpressed in early stages. Six out 11 were never been described in mouse embryology. Experiment Overall Design: Mouse embryos were collected at successive stages of early and adult development stages for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain homogeneous populations of NCCs by Laser Capture Microdissection (LCM) from embryos and adult in order to analyze DNA repair genes during mouse development. To that end, we collected cells at three time-points: at embryonal stage of 8.5 dpc: E8.5 (neural tube closure); at embryonal stage of 13.5dpc: E13.5 (dorsal root ganglion); at adult stage of 3 months postnatal: P90 (adrenal medulla).
2008-06-20 | E-GEOD-11356 | biostudies-arrayexpress
Project description:Neuroblastoma (NB) arises from neural crest cells (NCCs) secondary to a block in differentiation. Retinoic acid (RA) differentiation therapy has limited therapeutic efficacy, and the mechanisms preventing terminal differentiation remain elusive. We found that the chromatin modifier CHAF1A restricts neuronal differentiation and promotes NB oncogenesis. CHAF1A blocks NC differentiation into mature neurons in both human NCCs and zebrafish models. CHAF1A gain-of-function promotes cell malignancy, blocks RA-induced differentiation, and is sufficient to induce NB tumor formation. Mechanistically, CHAF1A blocks NB differentiation by repressing gene expression programs promoting neuronal development and differentiation, and rewiring polyamine metabolism. Targeting polyamine synthesis restores NB sensitivity to RA therapy. Our results demonstrate that CHAF1A critically contributes to NB oncogenesis by blocking neuronal differentiation and reprogramming cell metabolism.
2021-07-20 | GSE144311 | GEO
Project description:Pleiotropic genetic factors (e.g., DNA polymorphisms) may be involved in the initiation of neuroblastoma (NB) and coronary artery disease (CAD) given their common origin from defects in neural crest development. To discover novel NB susceptibility genes, we conducted a three-stage survey including a meta-analysis of NB and CAD genome-wide association data, prioritization of NB causal variants, and validation in an independent case-controls cohort. The lead SNP, rs13337397 at the 16q23.1 locus, associated with both diseases in the meta-analysis and with NB in the validation study. All the SNPs in linkage disequilibrium with rs13337397 were annotated using the H3K27ac epigenetic marker of neural crest cells (NCC) and NB cell lines. Indeed, we identified the functional SNP rs13337017, mapping within an enhancer of NCCs and NB cell lines and showing long-range interactions with CFDP1 by Hi-C analysis. Luciferase assays indicated that the risk allele of rs13337017 increased CFDP1 expression in NB cell lines. Of note, CFDP1 high expression associated with unfavorable prognostic markers in an analysis including 498 NB transcriptomes. Moreover, depletion of CFDP1 markedly decreased viability and migration and increased apoptotic rates in NB cell lines. Finally, transcriptome and qPCR analyses revealed that the depletion of CFDP1 may affect noradrenergic neuron differentiation by downregulating master regulators of sympathetic noradrenergic identity, including PHOX2B, HAND2 and GATA3. Our data strongly suggest that CFDP1 acts as oncogene in NB. Additionally, we provide evidence that genetic predisposition to NB can be mediated by the alteration of noradrenergic lineage-specific gene expression.
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Project description:Neural crest cells (NCCs) are a multipotent cell population that contributes to the development of many tissues including craniofacial, pharyngeal arch arteries, and cardiac outflow tract (OFT). The BAF complex plays an important role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, its role in neural crest development has remained unclear. To determine the role BAF complex, we deleted BAF155 and BAF170, the core subunits required for the assembly, stability, and functions of the BAF complex in NCCs. Mouse embryos lacking BAF155/170 in NCCs displayed early lethality due to a wide range of developmental defects including craniofacial defects, pharyngeal arch artery defects, and OFT defects. We observed reduced proliferation, increased cell death, and impaired migration of cardiac NCCs to the OFT in BAF155/170 mutants. RNAseq analysis on sorted NCCs revealed that the BAF complex regulates the expression of numerous genes essential for neural crest development. We observed downregulation of Hippo and Notch signaling pathways, both essential for the migration, proliferation, and differentiation of the NCCs. The BAF complex interacts with transcription factors to modulate the transcriptional program. Therefore, we performed transcription factor enrichment analysis on the RNAseq data set and identified several transcription factors including Hey1, Hey2, and Hes5 that may directly or indirectly interact with the BAF complex in NCCs. We also found that Brg1 interact with Tead transcription factors and the interaction was impaired in BAF155/170 knockdown cells. Together, our results demonstrate an important role of the BAF complex in modulating the gene regulatory network essential for neural crest development.
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Project description:Specialized chromatin-binding proteins are required for DNA-based processes during development. We recently established PWWP2A as a direct histone variant H2A.Z interactor involved in mitosis and craniofacial development. Here, we identify the H2A.Z/PWWP2A-associated protein HMG20A as part of several chromatin-modifying complexes, including NuRD, andshow that it localizes to distinct genomic regulatory regions. Hmg20a depletion causes severe head and heart developmental defects in Xenopus laevis. Our data indicate that craniofacial malformations are caused by defects in neural crest cell (NCC) migration and cartilage formation. These developmental failures are phenocopied in Hmg20a-depleted mESCs, which show inefficient differentiation into NCCs and cardiomyocytes (CM). Consequently, loss of HMG20A, which marks open promoters and enhancers, results in chromatin accessibility changes and a striking deregulation of transcription programs involved in epithelial-mesenchymal transition (EMT) and differentiation processes. Collectively, our findings implicate HMG20A as part of the H2A.Z/PWWP2A/NuRD-axis and reveal it as a key modulator of intricate developmental transcription programs that guide the differentiation of NCCs and CMs.
2023-03-11 | PXD038968 | Pride
Project description:Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating numerous transcripts from a single protein-coding gene. Tissue-specific regulators of AS are essential components of the gene regulatory network, required for normal cellular function, tissue patterning, and embryonic development. However, their cell-autonomous function in neural crest development has not been explored. Here, we demonstrate that splicing factor Rbfox2 is expressed in the neural crest cells (NCCs) and deletion of Rbfox2 in NCCs leads to cleft palate and defects in craniofacial bone development. RNA-Seq analysis revealed that Rbfox2 regulates splicing and expression of numerous genes essential for neural crest/craniofacial development. We demonstrate that Rbfox2-TGF-β-Tak1 signaling axis is deregulated by Rbfox2 deletion. Furthermore, restoration of TGF-β signaling by Tak1 overexpression can rescue the proliferation defect seen in Rbfox2 mutants. We also identified a positive feedback loop in which TGF-β signaling promotes expression of Rbfox2 in NCCs.
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Project description:S23 experiment: We sought to identify the microRNAs (miRNAs) enriched in the neural crest cell (NCC) population from E11.5 mouse embryos. To accomplish this, we utilized a transgenic mouse line harboring Cre-recombinase under the control of the Wnt1 NCC-specific promoter and also carrying the R26R-YFP allele. We sorted YFP+ (NCCs) and YFP- (non-NCCs) from E11.5 Wnt1Cre-R26R mouse embryos via FACS and compared the relative enrichment of miRNAs in the YFP+ population by miRNA microarray. 220 experiment: We sought to identify the microRNAs (miRNAs) enriched in the neural crest cell (NCC) population from E10.5 mouse embryos. To accomplish this, we utilized a transgenic mouse line harboring Cre-recombinase under the control of the Wnt1 NCC-specific promoter and also carrying the R26R-YFP allele. We sorted YFP+ (NCCs) and YFP- (non-NCCs) from E10.5 Wnt1Cre-R26R mouse embryos via FACS and compared the relative enrichment of miRNAs in the YFP+ population by miRNA microarray. 221 experiment: Our research has shown that heterozygous deletion of the miRNA processing enzyme Dicer leads to developmental delay of the thymus in mouse embryos. We sought to identify the microRNAs (miRNAs) affected by the loss of a single copy of Dicer in the neural crest cell (NCC) population from E10.5 mouse embryos. To accomplish this, we utilized a transgenic mouse line harboring a floxed allele of Dicer, Cre-recombinase under the control of the Wnt1 NCC-specific promoter, and also carrying the R26R-YFP allele. We sorted YFP+ (NCCs) cells from E10.5 Dicerfl/+,Wnt1Cre,R26R and Dicer+/+,Wnt1Cre,R26R mouse embryos via FACS and compared the relative expression of miRNAs in the Dicer-heterozygotes compared to Dicer-wildtypes by miRNA microarray. S23 experiment: RNA from YFP+ (NCCs) and YFP- (non-NCCs) cells sorted by FACS from E11.5 Wnt1Cre-R26R mouse embryos was isolated and hybridized to Exiqon miRNA microarrays v10. Cells from five E11.5 embryos were sorted into YFP+ and YFP- populations and pooled. 220 experiment: RNA from YFP+ (NCCs) and YFP- (non-NCCs) cells sorted by FACS from E10.5 Wnt1Cre-R26R mouse embryos was isolated and hybridized to Exiqon miRNA microarrays v10. Cells from ten E10.5 embryos were sorted into YFP+ and YFP- populations and pooled. 221 experiment: RNA from YFP+ (NCCs) cells sorted by FACS from E10.5 Dicerfl/+,Wnt1Cre,R26R and Dicer+/+,Wnt1Cre,R26R mouse embryos was isolated and hybridized to Exiqon miRNA microarrays v10. Cells from ten embryos were sorted into YFP+ populations and pooled for each genotype.
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Project description:The introduction and widespread adoption of induced pluripotent stem cell (iPSC) technology has opened new avenues for craniofacial regenerative medicine. Neural crest cells (NCCs) are the precursor population to many craniofacial structures, including dental and periodontal structures, and iPSC-derived NCCs may, in the near future, offer an unlimited supply of patient-specific cells for craniofacial repair interventions. Here, we used an established protocol involving simultaneous Wnt signaling activation and TGF-β signaling inhibition to differentiate three human iPSC lines to cranial NCCs. We then derived a putative craniofacial mesenchymal progenitor (PCMP) population with chondrogenic and osteogenic potential from cranial NCCs and investigated their similarity to widely studied human postnatal dental or periodontal stem/progenitor cells. PCMPs were quite distinct from both their precursor cells (NCCs) and bone-marrow mesenchymal stromal cells, a stromal population of mesodermal origin. Despite their similarity with dental stem/progenitor cells, PCMPS were clearly differentiated by a core set of 66 genes, including ACKR3 (CXCR7), whose expression (both at transcript and protein level) appear to be peculiar to PCMPs. Altogether, our data demonstrate the feasibility of craniofacial mesenchymal progenitor derivation from human iPSCs through a neural crest-intermediate and set the foundation for future studies regarding their full differentiation repertoire and their in vivo existence.
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