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

Feige Kaplan, PhD; Tara MacRae, BSc; Julie Comber, MSc; Stephane Gagnon, Msc; Robert Sladek, MD; Thomas J. Hudson, MD; Neil B. Sweezey, MD
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*From the McGill University Health Center-Montreal Children’s Hospital Research Institute and The Hospital for Sick Children, Toronto.

Correspondence to: Feige Kaplan, PhD, Associate Professor, Departments of Human Genetics and Pediatrics, McGill University, 4060 St. Catherine’s St, Room 236, Quebec PQ, Canada H3Z 2Z3; e-mail: fkaplan@www.debelle.mcgill.ca

Chest. 2002;121(3_suppl):90S. doi:10.1378/chest.121.3_suppl.90S
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Glucocorticoid stimulation of the surfactant system in the developing lung is mediated by the glucocorticoid receptor (GR). Seventy-five percent of mice homozygous for a targeted hypomorphic disruption in the GR gene (GRhypo) die shortly after birth and display immature morphology and atelectasis. Surviving GRhypo mice are normal and fertile. We used complementary DNA microarrays (n = 3) and Northern blot analysis to identify developmentally regulated genes that are differentially expressed in the lung at fetal day 18 (GRhypo-18) and postnatal day 1 in GRWT and GRhypo mice. Neonatal animals were divided into survivors (GRhypo/surv) and nonsurvivors (GRhypo/nonsurv). Multiple overlapping alterations in gene expression were observed when the three groups of GRhypo mice were compared to GRWT mice. We reported on 31 previously described genes the expression of which was dramatically altered in the GRhypo/nonsurv mice compared to GRWT mice. Of these genes, 17 were down-regulated and 14 were up-regulated in GRhypo/nonsurv mice. Numerous expressed sequence tags also showed dramatic changes in expression in GRhypo/nonsurv, GRhypo/surv, and GRhypo-18 mice. Eight of the 31 genes identified showed similar patterns of altered gene expression in all three GRhypo groups. These genes included the following: thioether-S-methyltransferase; glutathione peroxidase; prostacyclin synthase; connexin 31 (down-regulated in GRhypo mice); PG-M core protein; neuronatin; TopoIIα; and midkine (up-regulated in GRhypo mice). Among the 17 down-regulated genes in GRhypo/nonsurv mice, 12 were associated with a role in cell signaling and cell communication, 3 were associated with inflammatory response, and 2 were associated with steroid metabolism. Among the 14 genes up-regulated in GRhypo/nonsurv mice, 7 were associated with cell signaling, 2 were associated with cell migration, 4 were associated with cell growth and proliferation, and 1 was associated with basement membranes. Additional genes were up-regulated or down-regulated in GRhypo/surv mice compared to GRhypo/nonsurv mice. Moreover, even more dramatic changes in gene expression were observed when GRhypo-18 mice were compared to GRWT mice. These findings contribute to our understanding of the developmental processes that link glucocorticoid stimulation to critical downstream events in fetal lung maturation.

Abbreviation: GR = glucocorticoid receptor

This work was funded by the Canadian Institutes of Health Research.

For 2001–2002, Dr. Kaplan is on sabbatical and can be reached at feige.kaplan@ tch.harvard.edu




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