Differential expression of RNAs in E9 tuft rostrums with NTDs
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE75001 | GEO | 2016/05/04
SECONDARY ACCESSION(S): PRJNA302161
REPOSITORIES: GEO
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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:At an incidence of approximately 1/1000 births, neural tube defects (NTDs) comprise one of the most common and devastating congenital disorders. In an attempt to enhance and expand our understanding of neural tube closure, we undertook a high-throughput gene expression analysis of the neural tube as it was forming in the mouse embryo. Open and closed sections of the developing neural tube were micro-dissected from mouse embryos, and hybridized to Affymetrix mouse expression arrays. Clustering of genes differentially regulated in open and closed sections of the developing neural tube highlighted molecular processes previously recognized to be involved in neural tube closure and neurogenesis. Analysis of the genes in these categories identified potential candidates underlying neural tube closure. In addition, we identified approximately 25 novel genes, of unknown function, that were significantly up-regulated in the closed neural tube. Based on their expression patterns in the developing neural tube, five novel genes are proposed as interesting candidates for involvement in neurogenesis. The high-throughput expression analysis of the neural tube as it forms allows for better characterization of pathways involved in neural tube closure and neurogenesis, and hopefully will strengthen the foundation for further research along the pathways dictating neural tube development.
2014-01-01 | GSE39442 | GEO
Project description:Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway leads to defective anteroposterior patterning, resulting in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We report here that in C57BL/6C mouse embryonic stem cells (mESC), folate deficiency activates Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promotes the formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex to regulate the Wnt target gene transactivation through the Wnt-responsive elements. Moreover, the enhanced transcriptional activity of Gcm1 is found to be dependent on CREB binding protein. Lastly, in NTDs mouse models and low folate NTDs human brain samples, Gcm1 and Wnt/β-catenin target genes related to neural tube closure are specifically overexpressed. These results indicate that low folate promotes Wnt/β-catenin signaling via activating Gcm1, leading to aberrant vertebrate neural development
2018-12-27 | GSE124339 | GEO
Project description:Background: Neural tube defects (NTDs) are congenital malformations that occur when the neural tube fails to close properly during early embryonic development. However, the identity of affected celltypes and pathogenic mechanisms remain unclear due to the lack of clinical samples. Method: We utilized single-nucleus RNA sequencing to analyze 37,064 neural tube cells from NTDs and normal abortus at 14 and 15 gestational weeks. Multiplexed immunofluorescence staining was performed to further validate some phenotypes. Results: Firstly, we revealed that the most affected celltypes are excitatory neurons, inhibitory neurons, and astrocytes. We further elucidated that the main subtypes mediating abnormal development in NTDs is IGF2high subtypes in inhibitory neurons and MEG3high subtypes in astrocytes. Importantly, our findings highlighted IGF2 as a pivotal gene for abnormal development and abnormal cell-cell communications in NTDs. Conclusions: In summary, this study presents the first single-cell atlas of NTDs and provides new insights for further research into the underlying mechanisms of NTDs.
2024-05-15 | GSE266595 | GEO
Project description:Neural Tube Defects (NTDs) are serious health problems of infants, accounting for large proportion of live birth defects in infants and miscarriage in women worldwide. Although some epidemiologic studies suggest both genetic and environmental factors were involved in the progression of the diseases, the etiologies of NTDs are not well understood at present. The objective of our study was to generate and to compare mRNA profiles of NTDs with those of normal controls in the 2nd trimesters of pregnancy. Illumina microarray chips (beadarrays) were utilized to identify the altered mRNA transcripts in the organ samples recruited from Luliang Prefecture in Shanxi Province, China, which has the highest occurrence of NTDs in world. The beadarrays identified 101 un-regulated and 194 down-regulated mRNA transcripts in the NTDs compared with the controls in the spinal cord. A number of genes in the cholesterol biosynthesis pathway were down-regulated. In particular, SIRT2, a key regulator of cholesterol biosynthesis, was significantly down-regulated in NTD samples. Our findings provide evidences that, the decrease of cholesterol biosynthesis in the spinal cord of NTD may affect the neural tube closure in the affected fetuses.
2019-10-10 | GSE33111 | GEO
Project description:At an incidence of approximately 1/1000 births, neural tube defects (NTDs) comprise one of the most common and devastating congenital disorders. In an attempt to enhance and expand our understanding of neural tube closure, we undertook a high-throughput gene expression analysis of the neural tube as it was forming in the mouse embryo. Open and closed sections of the developing neural tube were micro-dissected from mouse embryos, and hybridized to Affymetrix mouse expression arrays. Clustering of genes differentially regulated in open and closed sections of the developing neural tube highlighted molecular processes previously recognized to be involved in neural tube closure and neurogenesis. Analysis of the genes in these categories identified potential candidates underlying neural tube closure. In addition, we identified approximately 25 novel genes, of unknown function, that were significantly up-regulated in the closed neural tube. Based on their expression patterns in the developing neural tube, five novel genes are proposed as interesting candidates for involvement in neurogenesis. The high-throughput expression analysis of the neural tube as it forms allows for better characterization of pathways involved in neural tube closure and neurogenesis, and hopefully will strengthen the foundation for further research along the pathways dictating neural tube development. Embryos were dissected at days E8.5 and E9.5, and the neuroepithelium/ neural tube were mechanically detached from underlying tissues, and then separated into two regions: 1) M-bM-^@M-^\open neuroepitheliumM-bM-^@M-^]: neuroepithelial tissue caudal to the open/closed junction, and 2) M-bM-^@M-^\closed neural tubeM-bM-^@M-^], extending from a somiteM-bM-^@M-^Ys breadth rostral to the open/closed junction, up to the level of the fifth- or sixth-to-last somite. Samples consisted of biological triplicates of RNA extract from the above tissues (pooled by litter, and representing a total of 111 embryos): E8.5 open neuroepithelium, E8.5 closed neural tube, E9.5 open neuroepithelium, and E9.5 closed neural tube. Thus, a total of 12 samples (representing 111 embryos) were hybridized to the GeneChip Mouse Genome 430 2.0 Array (Affymetrix Inc., Santa Clara, CA, USA). One of the samples (06, closed E8.5) deviated significantly from the others in quality assessment and was therefore removed from subsequent analysis and not submitted to GEO.
2014-01-01 | E-GEOD-39442 | biostudies-arrayexpress
Project description:Folic acid (FA) prevents neural tube defects (NTDs), but it remains unclear why many cases of human NTDs still occur despite FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal dietary FA status to regulate embryonic brain development. We determined that cranial NTDs in Tet1-/- embryos display higher penetrance in non-inbred than in inbred genetic backgrounds and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of mild cranial deformities in wild type and Tet1+/- offspring and altered DNA hypermethylation in Tet1-/- embryos primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene which exhibits increased promoter DNA methylation, thus mimicking a pseudo-FA deficiency. FA deficiency reveals an impact of Tet1 haploinsufficiency that contributes to DNA hypermethylation and susceptibility to NTDs. Overall, our study reveals that epigenetic dysregulation may underlie the resistance of NTDs to FA supplementation.
2024-10-24 | GSE275401 | GEO
Project description:Folic acid (FA) prevents neural tube defects (NTDs), but it remains unclear why many cases of human NTDs still occur despite FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal dietary FA status to regulate embryonic brain development. We determined that cranial NTDs in Tet1-/- embryos display higher penetrance in non-inbred than in inbred genetic backgrounds and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of mild cranial deformities in wild type and Tet1+/- offspring and altered DNA hypermethylation in Tet1-/- embryos primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene which exhibits increased promoter DNA methylation, thus mimicking a pseudo-FA deficiency. FA deficiency reveals an impact of Tet1 haploinsufficiency that contributes to DNA hypermethylation and susceptibility to NTDs. Overall, our study reveals that epigenetic dysregulation may underlie the resistance of NTDs to FA supplementation.
2024-10-24 | GSE275393 | GEO
Project description:This data series was used for two separate studies. The initial study was aimed to idenify expression changes brought about by the Cecr2Gt45Bic mutation during neural closure. The study included two different strains, BALB/cCrl in which Cecr2GT45Bic shows a neural tube defect phenotype and FVB/N in which Cecr2Gt45Bic does not manifest neural closure defects. The second was to idenify strain specific expression differences present during neural closure of the mouse embryo between BALB/cCrl and FVB/N in order to identify candidate modifiers of the Cecr2Gt45Bic neural tube defect. Relevant abstracts are included below. The initial study ; BACKGROUND: Over 200 mouse genes are associated with neural tube defects (NTDs), including Cecr2, the bromodomain-containing subunit of the CERF chromatin remodeling complex. METHODS: Gene-trap mutation Cecr2Gt45Bic results in 74% exencephaly (equivalent of human anencephaly) on the BALB/c strain. Gene expression altered during cranial neural tube closure by the Cecr2 mutation was identified through microarray analysis of 11M-bM-^@M-^S14 somites stage Cecr2Gt45Bicembryos. RESULTS: Analysis of Affymetrix Mouse 430 2.0 chips detected 60 transcripts up-regulated and 54 transcripts down-regulated in the Cecr2Gt45Bic embryos (fold > 1.5, p < 0.05). The Cecr2 transcript was reduced only M-bM-^HM-<7- to 14-fold from normal levels, suggesting the Cecr2Gt45Bic is a hypomorphic mutation. We therefore generated a novel Cecr2 null allele (Cecr2tm1.1Hemc). Resulting mutants displayed a stronger penetrance of exencephaly than Cecr2Gt45Bic in both BALB/c and FVB/N strains, in addition to midline facial clefts and forebrain encephalocele in the FVB/N strain. The Cecr2 transcript is reduced 260-fold in the Cecr2tm1.1Hemc line. Subsequent qRT-PCR using Cecr2tm1.1Hemc mutant heads confirmed downregulation of transcription factors Alx1/Cart1,Dlx5, Eya1, and Six1. CONCLUSIONS: As both Alx1/Cart1 and Dlx5 mouse mutations result in exencephaly, we hypothesize that changes in expression of these mesenchymal/ectodermal transcription factors may contribute to NTDs associated with Cecr2. Birth Defects Research (Part A), 2010. 010 Wiley-Liss, Inc. The second study: ABSTRACT:Although neural tube defects (NTDs) are common in humans, little is known about their multifactorial genetic causes. While most mouse models involve NTDs caused by a single mutated gene, we have previously described a multigenic system involving susceptibility to NTDs. In mice with a mutation in Cecr2, the cranial NTD exencephaly shows strain specific differences in penetrance, with 74% penetrance in BALB/cCrl and 0% penetrance in FVB/N. Whole genome linkage analysis showed that a region of chromosome 19 was partially responsible for this difference in penetrance. We now reveal by genetic analysis of three subinterval congenic lines that the chromosome 19 region contains more than one modifier gene. Analysis of embryos showed that although a Cecr2 mutation causes wider neural tubes in both strains, FVB/N embryos overcome this abnormality and close. A microarray analysis comparing neurulating female embryos from both strains identified differentially expressed genes within the chromosome 19 region, including Arhgap19, which is expressed at a lower level in BALB/cCrl due to a stop codon specific to that substrain. Modifier genes in this region are of particular interest because it is syntenic to human chromosome 10q25, the site of a human susceptibility locus. (MANUSCRIPT PENDING SUBMISSION) Thieler STAGE 13-14 (11-14 somite) female embryos where disected away from extraembryonic membranes for RNA extraction and hybridization on Affymetrix microarrays. A single embryo was processed per array, with four biological replicates per genotype BALB/cCrl, Cecr2GT45Bic BALB/cCrl, FVB/N, and Cecr2Gt45Bic FVB/N.
2012-02-27 | E-GEOD-30957 | biostudies-arrayexpress
Project description:The closure of an open anatomical structure by the directed growth and fusion of two tissue masses is a recurrent theme in mammalian embryology, and this process plays an integral role in the development of the palate, ventricular septum, neural tube, urethra, diaphragm, and eye. In mice, targeted mutations of the genes encoding frizzled1 (Fz1) and frizzled2 (Fz2) show that these highly homologous integral membrane receptors play an essential and partially redundant role in closure of the palate and ventricular septum, and in the correct positioning of the cardiac outflow tract. When combined with a mutant allele of the planar cell polarity (PCP) gene Vangl2 (Vangl2Lp), Fz1 and/or Fz2 mutations also cause defects in neural tube closure and mis-orientation of inner ear sensory hair cells. These observations indicate that frizzled signaling is involved in diverse tissue closure processes, defects in which account for some of the most common congenital anomalies in humans. Microdissect E13.5 palates from Fz1-/-;Fz2+/+ and Fz1-/-;Fz2-/- embryos and compare transcript abundances by hybridization to Affymetrix 430 2.0 gene chips Supplementary file below reports fold change data.
2010-09-22 | E-GEOD-24276 | biostudies-arrayexpress