Application of Expression Microarrays to the Investigation of Fetal Lung Development in a Glucocorticoid Receptor Knockout Mouse Model

Kaplan, Feige; MacRae, Tara; Comber, Julie; Gagnon, Stéphane; Sladek, Robert; Hudson, Thomas J.; Sweezey, Neil

doi:10.1016/s0012-3692(15)35497-0

Cited by 4 publications

(3 citation statements)

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“…Genetic deletion of the corticosteroid receptor in mice reveals no abnormalities in liver histology. Neonate mice die from pulmonary hemorrhage 33. This suggests that in the absence of glucocorticoid receptor, other receptors also bound by corticosteroids (e.g.…”

Section: Discussionmentioning

confidence: 99%

HGF-, EGF-, and Dexamethasone-Induced Gene Expression Patterns During Formation of Tissue in Hepatic Organoid Cultures

Michalopoulos

Bowen²,

Mulé³

et al. 2003

gene expr

118

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Corticosteroids, hepatocyte growth factor (HGF), and epidermal growth factor (EGF) play important roles in hepatic biology. We have previously shown that these molecules are required for formation of tissue with specific histology in complex organoid cultures. Dexamethasone suppresses growth and induces hepatocyte maturation; HGF and EGF are needed for formation of the nonepithelial elements. All three are needed for formation of the biliary epithelium. The gene expression patterns by which corticosteroids, HGF, and EGF mediate their effects in hepatic tissue formation are distinct. These patterns affect many gene families and are described in detail. In terms of main findings, dexamethasone induces expression of both HNF4 and C/EBPα, essential transcription factors for hepatocyte differentiation. It suppresses hepatocyte growth by suppressing many molecules associated with growth in liver and other tissues, including IL-6, CXC-chemokine receptor, amphiregulin, COX-2, HIF, etc. HGF and EGF induce all members of the TGF-β family. They also induced multiple CNS-related genes, probably associated with stellate cells. Dexamethasone, as well as HGF and EGF, induces expression of HNF6-β, associated with biliary epithelium formation. Combined addition of all three molecules is associated with mature histology in which hepatocyte and biliary lineages are separate and HNF4 is expressed only in hepatocyte nuclei. In conclusion, the results provide new and surprising information on the gene expression alterations by which corticosteroids, HGF, and EGF exert their effects on formation of hepatic tissue. The results underscore the usefulness of the organoid cultures for generating information on histogenesis, which cannot be obtained by other culture or whole animal models. Gene arraysThree-dimensional cultures Hepatocytes Biliary cells Growth regulation HEPATOCYTES isolated by perfusion of rat liver thelium in the surface of these cultures is in large part derived from hepatocytes undergoing trans-differenwith collagenase contain a small contaminant population of other hepatic cells, such as stellate cells, bilitiation (45). HGF and EGF are required for the formation of the biliary epithelium and the connective ary epithelium, endothelial cells, etc. The primary isolates reorganize to form tissue with recognizable, albeit tissue. The effects on connective tissue are probably mediated by regulation of expression of TGF-β famaltered, hepatic microarchitecture in roller bottle cultures under the influence of insulin, nicotinamide, corily members (46). Dexamethasone, in the absence of HGF and EGF, induces maturation of cells excluticosteroids (dexamethasone), hepatocyte growth factor (HGF), and epidermal growth factor (EGF). Histology sively towards the hepatocytic lineage. Biliary epithelium is absent without addition of HGF or EGF. in these organoid cultures consists of a surface layer of mature biliary epithelium, an intermediate layer ofWhen dexamethasone, HGF, and EGF are all removed, immature hepatocytes present in the cu...

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Section: Discussionmentioning

confidence: 99%

HGF-, EGF-, and Dexamethasone-Induced Gene Expression Patterns During Formation of Tissue in Hepatic Organoid Cultures

Michalopoulos

Bowen²,

Mulé³

et al. 2003

gene expr

118

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“…The application of microarray technology to the study of gene expression in the lung has followed three main themes: (1) normal physiological function, (2) differentiation of disease processes, and (3) insult or injury to lung tissues. The study of normal physiological function of the lung has included genes turned on at different stages of development 84,85 and genes expressed as a result of introducing specific genes with known biological properties. 86,87 For example, using primary cultures of welldifferentiated human airway epithelial cells, downstream effects of the keratinocyte growth factor (KGF) gene, known to regulate several functions in adult and developing lung epithelia, were studied.…”

Section: Oligonucleotide Microarrays: Mining the Genome For Goldmentioning

confidence: 99%

Genetic Epidemiological Approaches to the Study of Lung Disease

Rybicki¹

2003

Seminars in Respiratory and Critical Care Medicine

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The DNA sequence data provided by the Human Genome Project offer great promise in the prevention and treatment of lung disease in the new millennium. Making sense of these data with regard to how they relate to disease susceptibility and progression will require new and innovative genetic epidemiological approaches. Although tried and true methodologies such as case-control comparisons are still useful, a better understanding of genotype-phenotype relationships in lung disease can be gained by comparisons across similar diseases, such as the HLA-DPB1 associations observed in both berylliosis and sarcoidosis. Study of gene-environment and gene-gene interactions in lung disease is critical to the understanding of pathogenic processes in the lung such as localized inflammation and malignant transformation. Oligonucleotide microarray studies of gene expression in the lung are well under way and promise to uncover numerous previously unknown genetic factors involved in lung pathogenesis. One of the greatest challenges facing genetic epidemiologists studying lung disease in the new millennium will be how to translate the myriad results from microarray and similar data-driven technologies into information useful to the medicine practiced in pulmonary clinics.

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“…As an alternative approach for understanding the molecular regulation of sacculation, it is reasonable to compare lungs with normal alveolar sac formation to those with altered sac formation and infer from differences in gene expression a set of candidate genes involved in the process. Preliminary expression microarray analysis of the GR knockout lung [ 16 ] has explored the overall changes in gene expression that lead to alterations in alveolar sac formation. This approach has also been used to study the related process of alveologenesis, that involves formation of septae that 'subdivide' alveolar sacs into smaller units or true alveoli [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Alterations in gene expression in T1α null lung: a model of deficient alveolar sac development

et al. 2006

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BackgroundDevelopment of lung alveolar sacs of normal structure and size at late gestation is necessary for the gas exchange process that sustains respiration at birth. Mice lacking the lung differentiation gene T1α [T1α(-/-)] fail to form expanded alveolar sacs, resulting in respiratory failure at birth. Since little is known about the molecular pathways driving alveolar sacculation, we used expression microarrays to identify genes altered in the abnormal lungs and, by inference, may play roles in normal lung morphogenesis.ResultsAltered expression of genes related to cell-cell interaction, such as ephrinA3, are observed in T1α(-/-) at E18.5. At term, FosB, Egr1, MPK-1 and Nur77, which can function as negative regulators of the cell-cycle, are down-regulated. This is consistent with the hyperproliferation of peripheral lung cells in term T1α (-/-) lungs reported earlier. Biochemical assays show that neither PCNA nor p21 are altered at E18.5. At term in contrast, PCNA is increased, and p21 is decreased.ConclusionThis global analysis has identified a number of candidate genes that are significantly altered in lungs in which sacculation is abnormal. Many genes identified were not previously associated with lung development and may participate in formation of alveolar sacs prenatally.

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Application of Expression Microarrays to the Investigation of Fetal Lung Development in a Glucocorticoid Receptor Knockout Mouse Model

Cited by 4 publications

References 0 publications

HGF-, EGF-, and Dexamethasone-Induced Gene Expression Patterns During Formation of Tissue in Hepatic Organoid Cultures

HGF-, EGF-, and Dexamethasone-Induced Gene Expression Patterns During Formation of Tissue in Hepatic Organoid Cultures

Genetic Epidemiological Approaches to the Study of Lung Disease

Alterations in gene expression in T1α null lung: a model of deficient alveolar sac development

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