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MicroRNA gene expression signatures in the developing neural tube.

ABSTRACT: Neurulation requires precise, spatio-temporal expression of numerous genes and coordinated interaction of signal transduction and gene regulatory networks, disruption of which may contribute to the etiology of neural tube defects (NTDs). MicroRNAs (miRNAs) are key modulators of cell and tissue differentiation. To define potential roles of miRNAs in development of the murine neural tube (NT), miRNA microarray analysis was conducted to establish expression profiles, and identify miRNA target genes and functional gene networks.The miRNA expression profiles in murine embryonic NTs derived from gestational days 8.5, 9.0, and 9.5 were defined and compared utilizing miRXplore microarrays from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany. Gene expression changes were verified by TaqMan quantitative Real-Time PCR. The clValid R package and the UPGMA (hierarchical) clustering method were utilized for cluster analysis of the microarray data. Functional associations among selected miRNAs were examined via Ingenuity Pathway Analysis.The miRXplore chips enabled examination of 609 murine miRNAs. Expression of approximately 12% of these was detected in murine embryonic NTs. Clustering analysis revealed several developmentally regulated expression clusters among these expressed genes. Target analysis of differentially expressed miRNAs enabled identification of numerous target genes associated with cellular processes essential for normal NT development. Utilization of Ingenuity Pathway Analysis revealed interactive biologic networks which connected differentially expressed miRNAs with their target genes, and highlighted functional relationships.The present study defined unique gene expression signatures of a range of miRNAs in the developing NT during the critical period of NT morphogenesis. Analysis of miRNA target genes and gene interaction pathways revealed that specific miRNAs might direct expression of numerous genes encoding proteins, which have been shown to be indispensable for normal neurulation. This study is the first to identify miRNA expression profiles and their potential regulatory networks in the developing mammalian NT.

SUBMITTER: Mukhopadhyay P

PROVIDER: S-EPMC3165006 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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MicroRNA gene expression signatures in the developing neural tube.

Mukhopadhyay Partha P Brock Guy G Appana Savitri S Webb Cynthia C Greene Robert M RM Pisano M Michele MM

Birth defects research. Part A, Clinical and molecular teratology 20110718 8

<h4>Background</h4>Neurulation requires precise, spatio-temporal expression of numerous genes and coordinated interaction of signal transduction and gene regulatory networks, disruption of which may contribute to the etiology of neural tube defects (NTDs). MicroRNAs (miRNAs) are key modulators of cell and tissue differentiation. To define potential roles of miRNAs in development of the murine neural tube (NT), miRNA microarray analysis was conducted to establish expression profiles, and identify ...[more]

PMID: 21770019

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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.

Project description:BACKGROUND: Development of the neural tube is a highly orchestrated process relying on precise, spatio-temporal expression of numerous genes as well as hierarchies of signal transduction and gene regulatory networks. Disruption of expression of a number of genes participating in these networks is believed to underlie developmental anomalies such as neural tube defects (NTDs) resulting from anomalous neural tube morphogenesis. MicroRNAs (miRNAs), a large family of noncoding RNAs, have been shown to function as gene silencers, and thus, are key modulators of cell and tissue differentiation. To elucidate potential roles of miRNAs in murine neural tube development, miRNA gene expression profiling has been utilized in the current study, to garner novel and in-depth knowledge on the expression and regulation of genes encoding miRNAs as well as their potential target genes governing maturation of the mammalian neural tube. METHODS: With the aim of identifying differentially expressed miRNAs during mammalian neural tube ontogenesis, miRNA expression profiles from gestation day (GD) -8.5, -9.0 and -9.5 murine neural tube tissue were compared utilizing miRXplore™ microarrays from Miltenyi Biotech GmbH. Gene expression changes observed in microarray analysis were verified by TaqManTM quantitative Real-Time PCR. clValid R package and the UPGMA (hierarchical) clustering method were utilized for cluster analysis of the microarray data. Functional associations among selected miRNAs were examined exploiting Ingenuity Pathway Analysis. RESULTS: Expression of approximately 12% of the 609 murine miRNA genes examined was detected in murine neural tube tissues from GD -8.5, -9.0 and -9.5. Clustering analysis revealed several developmentally regulated clusters among these expressed genes. MicroRNA target analysis enabled identification of a panoply of protein-coding target genes of the differentially expressed miRNAs within such clusters. Interestingly, many of these target genes have been shown to be associated with vital cellular processes such as cell proliferation, cell adhesion, cell migration, differentiation, apoptosis and epithelial-mesenchymal transformation, all of which are essential for normal neural tube development. Utilization of Ingenuity Pathway Analysis (IPA; Ingenuity Systems) allowed identification of interactive biological networks connecting differentially expressed miRNAs and their target genes highlighting functional relationships. CONCLUSIONS: In the present study, a unique gene expression signature of a range of miRNAs in embryonic neural tube tissue was delineated. Analysis of miRNA target genes and gene interaction pathways emphasized that expression of numerous protein-encoding genes, indispensable for normal neural tube morphogenesis, may be regulated by specific miRNAs.

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MicroRNA gene expression signatures in the developing neural tube.

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MicroRNA gene expression signatures in the developing neural tube.

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