Purpose: Mutations in several genetic loci lead to cardiac anomalies, with mutations in transcription factor NKX2-5 gene being one of the largest mutations known. Gestational hypoxia, such as seen in high-altitude pregnancy, has been known to affect cardiac development, and this paper aims to uncover information about the underlying mechanisms of this phenomena. Methods: Wild-type female mice were mated with Nkx2-5 mutant males, to produce offsprings. The pregnant females were then separated into two groups, one left in normal air and one breathing hypoxic, 14% oxygen, air from gestation day 10.5 to 12.5. Hearts were dissected from E12.5 embryos, subjected to RNA purification followed by RNA-seq. Wild-hypoxia and mutant-normoxia were compared to control wild-normoxia. Conclusions: The results of our study provide insights into a common molecular mechanism underlying non-genetic/epigenetic and genetic cardiac anomalies. Overall design: Embryonic mice were produced with either wild-type or mutant genomes, and some from each group were exposed to hypoxia during gestation, then physical analysis and RNA sequencing was done on the embryos.
Mechanism Sharing Between Genetic and Gestational Hypoxia-Induced Cardiac Anomalies.
Specimen part, Treatment, Subject
View SamplesTo elucidate the mode of action of apratyramide, we performed microarray profiling using the Affymetrix GeneChip Human Transcriptome Array 2.0 to determine global changes in transcript levels in HaCaT cells treated with apratyramide. Comparativel analysis identified 371 differentially expressed genes after 12 h treatment with 30 M apratyramide (p < 0.05, FDR corrected, fold change >1.5 or <0.67). Consistent with our previous data, VEGF-A appeared to be one of the most up-regulated genes. To examine the molecular functions and genetic networks, the microarray data was analyzed using Ingenuity Pathways Aanalysis (IPA).The global changes of transcript levels are associated with increased downstream phenotypic effects including angiogenesis, mitogenesis, differentiation of epithelial tissue and formation of skin, and decreased effects such as apoptosis of liver cells and hypoplasia of organs. IPA analysis of 371 microarray hits indicated the unfolded protein response (UPR) as the top canonical pathway with a p-value of 1.45 10-16. The IPA also elucidated that the 371 hits were most related to a molecular network associated with the function of cellular compromise and cellular maintenance. The network contains molecular components from UPR pathway, NRF2-mediated oxidative stress response signaling as well as glucocorticoid receptor signaling.
Apratyramide, a Marine-Derived Peptidic Stimulator of VEGF-A and Other Growth Factors with Potential Application in Wound Healing.
Treatment
View SamplesOne of the key questions in developmental biology is how from universally shared molecular mechanisms and pathways, is it possible to generate organs displaying similar or complementary functions, with a wide range of different shapes or tissue organization? The dentition represents a valuable system to address the issues of differential molecular signatures generating specific tooth types. We performed a comparative transcriptomic analysis of developing murine lower incisors, mandibular molars and maxillary molars at the developmental cap stage (E14.5) prior to recognizable tooth shape and cusp pattern.
Molars and incisors: show your microarray IDs.
Specimen part
View SamplesTranscriptome analysis of nucleus accumbens shell samples from RAR-null mutant mice and their wild type littermates
Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders.
Sex
View SamplesRetinoic acid (RA), an active derivative of the liposoluble vitamin A (retinol), acts as an important signaling molecule during embryonic development, regulating phenomenons as diverse as anterior-posterior axial patterning, forebrain and optic vesicle development, specification of hindbrain rhombomeres, pharyngeal arches and second heart field, somitogenesis, and differentiation of spinal cord neurons. This small molecule directly triggers gene activation by binding to nuclear receptors (RARs), switching them from potential repressors to transcriptional activators. The repertoire of RA-regulated genes in embryonic tissues is poorly characterized. We performed a comparative analysis of the transcriptomes of murine wild-type and Retinaldehyde Dehydrogenase 2 null-mutant (Raldh2-/-) embryos - unable to synthesize RA from maternally-derived retinol - using Affymetrix DNA microarrays. Transcriptomic changes were analyzed in two embryonic regions: anterior tissues including forebrain and optic vesicle, and posterior (trunk) tissues, at early stages preceding the appearance of overt phenotypic abnormalities. Several genes expected to be downregulated under RA deficiency appeared in the transcriptome data (e.g. Emx2, Foxg1 anteriorly, Cdx1, Hoxa1, Rarb posteriorly), whereas reverse-transcriptase-PCR and in situ hybridization performed for additional selected genes validated the changes identified through microarray analysis. Altogether, the affected genes belonged to numerous molecular pathways and cellular/organismal functions, demonstrating the pleiotropic nature of RA-dependent events. In both tissue samples, genes upregulated were more numerous than those downregulated, probably due to feedback regulatory loops. Bioinformatic clustering analysis allowed us to extract groups of genes displaying similar behaviors in mutant tissue samples. These data give an overview of the gene expression changes occurring under a state of embryonic RA deficiency, and provide new candidate genes and pathways for a better understanding of retinoid-dependent molecular events.
Transcriptomic analysis of murine embryos lacking endogenous retinoic acid signaling.
Specimen part
View SamplesWe determined the Taf4 dependent differential expression of RNAs in WT as well as KO cells in their pluripotent state, before and after treatment with retinoic acid and immediately before plating to form neuronal precursors. Overall design: Examination of RNA expression in 4 different cell lines (2 independent Taf4 WT and 2 independent Taf4 KO) in ES cells and at 3 timepoints during differentiation into neurons.
Essential role of the TFIID subunit TAF4 in murine embryogenesis and embryonic stem cell differentiation.
No sample metadata fields
View SamplesWe determined the Taf4 dependent differential expression of RNAs in WT as well as KO cells at day 9 of the differentiation into the cardiac lineage. Overall design: Examination of RNA expression in 4 different cell lines (2 independent Taf4 WT and 2 independent Taf4 KO) in 1 timepoint during cardiac differentiation.
Essential role of the TFIID subunit TAF4 in murine embryogenesis and embryonic stem cell differentiation.
No sample metadata fields
View SamplesTotal RNA samples from Vax2 knockout mouse eyes (at least two biological replicates) were profiled by gene expression. As control we used total RNA from wild type eyes. The analysis was carried out at five different developmental stages: E10.5, E12.5, E16.5, P8, and P60.
Vax2 regulates retinoic acid distribution and cone opsin expression in the vertebrate eye.
Specimen part
View SamplesThe RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked monogenic disease associating severe learning deficit andassociated to typical facial and digital abnormalities and skeletal changes. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized.
RSK2 is a modulator of craniofacial development.
No sample metadata fields
View SamplesLifelong murine gene expression profiles in relation to chronological and biological aging in multiple organs
Life spanning murine gene expression profiles in relation to chronological and pathological aging in multiple organs.
Age, Specimen part
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