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Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation.

ABSTRACT: BACKGROUND: Insulin-like Growth Factor 1 (IGF1) is a multifunctional regulator of somatic growth and development throughout evolution. IGF1 signaling through IGF type 1 receptor (IGF1R) controls cell proliferation, survival and differentiation in multiple cell types. IGF1 deficiency in mice disrupts lung morphogenesis, causing altered prenatal pulmonary alveologenesis. Nevertheless, little is known about the cellular and molecular basis of IGF1 activity during lung development. METHODS/PRINCIPAL FINDINGS: Prenatal Igf1(-/-) mutant mice with a C57Bl/6J genetic background displayed severe disproportional lung hypoplasia, leading to lethal neonatal respiratory distress. Immuno-histological analysis of their lungs showed a thickened mesenchyme, alterations in extracellular matrix deposition, thinner smooth muscles and dilated blood vessels, which indicated immature and delayed distal pulmonary organogenesis. Transcriptomic analysis of Igf1(-/-) E18.5 lungs using RNA microarrays identified deregulated genes related to vascularization, morphogenesis and cellular growth, and to MAP-kinase, Wnt and cell-adhesion pathways. Up-regulation of immunity-related genes was verified by an increase in inflammatory markers. Increased expression of Nfib and reduced expression of Klf2, Egr1 and Ctgf regulatory proteins as well as activation of ERK2 MAP-kinase were corroborated by Western blot. Among IGF-system genes only IGFBP2 revealed a reduction in mRNA expression in mutant lungs. Immuno-staining patterns for IGF1R and IGF2, similar in both genotypes, correlated to alterations found in specific cell compartments of Igf1(-/-) lungs. IGF1 addition to Igf1(-/-) embryonic lungs cultured ex vivo increased airway septa remodeling and distal epithelium maturation, processes accompanied by up-regulation of Nfib and Klf2 transcription factors and Cyr61 matricellular protein. CONCLUSIONS/SIGNIFICANCE: We demonstrated the functional tissue specific implication of IGF1 on fetal lung development in mice. Results revealed novel target genes and gene networks mediators of IGF1 action on pulmonary cellular proliferation, differentiation, adhesion and immunity, and on vascular and distal epithelium maturation during prenatal lung development.

SUBMITTER: Pais RS

PROVIDER: S-EPMC3877002 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation.

Pais Rosete Sofía RS Moreno-Barriuso Nuria N Hernández-Porras Isabel I López Icíar Paula IP De Las Rivas Javier J Pichel José García JG

PloS one 20131231 12

<h4>Background</h4>Insulin-like Growth Factor 1 (IGF1) is a multifunctional regulator of somatic growth and development throughout evolution. IGF1 signaling through IGF type 1 receptor (IGF1R) controls cell proliferation, survival and differentiation in multiple cell types. IGF1 deficiency in mice disrupts lung morphogenesis, causing altered prenatal pulmonary alveologenesis. Nevertheless, little is known about the cellular and molecular basis of IGF1 activity during lung development.<h4>Methods ...[more]

PMID: 24391734

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Project description:Fatty acids (FA) in ruminants, especially unsaturated FA (USFA) have important impact in meat quality, nutritional value, and flavour quality of meat, and on consumer's health. Identification of the genetic factors controlling the FA composition and metabolism is pivotal to select sheep that produce higher USFA and lower saturated (SFA) for the benefit of sheep industry and consumers. Therefore, this study was aimed to investigate the transcriptome profiling in the liver tissues collected from sheep with divergent USFA content in longissimus muscle using RNA deep-sequencing. From sheep (n = 100) population, liver tissues with higher (n = 3) and lower (n = 3) USFA content were analysed using Illumina HiSeq 2500. The total number of reads produced for each liver sample were ranged from 21.28 to 28.51 million with a median of 23.90 million. Approximately, 198 genes were differentially regulated with significance level of p-adjusted value <0.05. Among them, 100 genes were up-regulated, and 98 were down-regulated (p<0.01, FC>1.5) in the higher USFA group. A large proportion of key genes involved in FA biosynthesis, adipogenesis, fat deposition, and lipid metabolism were identified, such as APOA5, SLC25A30, GFPT1, LEPR, TGFBR2, FABP7, GSTCD, and CYP17A. Pathway analysis revealed that glycosaminoglycan biosynthesis- keratan sulfate, adipokine signaling, galactose metabolism, endocrine and other factors-regulating calcium metabolism, mineral metabolism, and PPAR signaling pathway were playing important regulatory roles in FA metabolism. Importantly, polymorphism and association analyses showed that mutation in APOA5, CFHR5, TGFBR2 and LEPR genes could be potential markers for the FA composition in sheep. These polymorphisms and transcriptome networks controlling the FA variation could be used as genetic markers for FA composition-related traits improvement. However, functional validation is required to confirm the effect of these SNPs in other sheep population in order to incorporate them in the sheep breeding program.

Project description:BackgroundEucalyptus, a highly diverse genus of the Myrtaceae family, is the most widely planted hardwood in the world due to its increasing importance for fiber and energy. Somatic embryogenesis (SE) is one large-scale method to provide commercial use of the vegetative propagation of Eucalyptus and dedifferentiation is a key step for plant cells to become meristematic. However, little is known about the molecular changes during the Eucalyptus SE.ResultsWe compared the transcriptome profiles of the differentiated and dedifferentiated tissues of two Eucalyptus species - E. camaldulensis (high embryogenetic potential) and E. grandis x urophylla (low embryogenetic potential). Initially, we identified 18,777 to 20,240 genes in all samples. Compared to the differentiated tissues, we identified 9229 and 8989 differentially expressed genes (DEGs) in the dedifferentiated tissues of E. camaldulensis and E. grandis x urophylla, respectively, and 2687 up-regulated and 2581 down-regulated genes shared. Next, we identified 2003 up-regulated and 1958 down-regulated genes only in E. camaldulensis, including 6 somatic embryogenesis receptor kinase, 17 ethylene, 12 auxin, 83 ribosomal protein, 28 zinc finger protein, 10 heat shock protein, 9 histone, 122 cell wall related and 98 transcription factor genes. Genes from other families like ABA, arabinogalactan protein and late embryogenesis abundant protein were also found to be specifically dysregulated in the dedifferentiation process of E. camaldulensis. Further, we identified 48,447 variants (SNPs and small indels) specific to E. camaldulensis, including 13,434 exonic variants from 4723 genes (e.g., annexin, GN, ARF and AP2-like ethylene-responsive transcription factor). qRT-PCR was used to confirm the gene expression patterns in both E. camaldulensis and E. grandis x urophylla.ConclusionsThis is the first time to study the somatic embryogenesis of Eucalyptus using transcriptome sequencing. It will improve our understanding of the molecular mechanisms of somatic embryogenesis and dedifferentiation in Eucalyptus. Our results provide a valuable resource for future studies in the field of Eucalyptus and will benefit the Eucalyptus breeding program.

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Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation.

Publications

Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation.

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