Biomedical subjects

Stéphane Gagnon

Publications and source records attributed to Stéphane Gagnon.

2 recordsLinked to original sources

PubMed2003

The growth factor midkine is modulated by both glucocorticoid and retinoid in fetal lung development.

The glucocorticoids (GC) and retinoids (RA) modulate branching morphogenesis and cytodifferentiation in the developing lung. We investigated downstream target genes that link glucocorticoid stimulation to the achievement of a mature lung in glucocorticoid receptor (GR) knockout mice. All GR(null) mice and approximately 80% of mice homozygous for a hypomorphic allele (GR(hypo)) die shortly after birth of respiratory failure. cDNA microarray analysis showed organ-specific upregulation of the retinoic acid responsive gene midkine (MK) and its chondroitin-sulfate binding partner PG-M/versican at fetal day 18 and at neonatal day 1 in lungs of GR(hypo) mice, and at neonatal day 1 in lungs of GR(null) mice. By contrast, lung MK and PG-M/versican were downregulated in these mice at fetal day 16.5. In situ hybridization studies showed a dramatic decrease in MK and PG-M/versican RNA between days 16.5 and 17.5 in GR(WT) but not in GR(null) mice. Continued diffuse and robust expression of MK protein was observed in GR(null) mice at neonatal day 1. These findings suggest that MK may contribute to the dysmature lung phenotype in GR-deficient mice. Exposure of cultured day 21 fetal rat lung cells to GC downregulated MK, whereas RA enhanced MK expression. Our findings demonstrate the coincident modulation of expression of MK at the same developmental time point by both GC and RA, providing a potential mechanism for the integration of GC and RA effects on fetal lung development.

Animals↗

PubMed2003

Antisense oligodeoxynucleotides decrease LGL1 mRNA and protein levels and inhibit branching morphogenesis in fetal rat lung.

We previously described the cloning of the late gestation lung 1 gene (LGL1), a novel glucocorticoid-inducible gene expressed in the mesenchyme of fetal lung. We report here evidence for a role of the LGL1 gene product (lgl1) in fetal rat lung airway branching morphogenesis, temporal and spatial localization of LGL1 mRNA and lgl1 protein in fetal rat lung, and a correction of the previously published LGL1 sequence. Both the mRNA and protein were detected during fetal lung development. LGL1 mRNA was detected from gestational Day 12 by reverse transcriptase-polymerase chain reaction, and from Day 13 by in situ hybridization. lgl1 protein was detected from Day 18 by Western analysis and from Day 16 by immunohistochemistry. The types of cells expressing LGL1 mRNA and lgl1 protein were assessed by immunohistochemical staining of adjacent serial tissue sections for markers of mesenchymal (vimentin) and smooth muscle (alpha-actin) cells. As gestation advanced, increasing amounts of mRNA and protein were expressed in these cells. In support of a role for lgl1 in airway branching morphogenesis, antisense (but neither sense nor scrambled) oligodeoxynucleotides directed against LGL1 inhibited airway branching in fetal rat lung buds in explant culture, in a dose- and time-dependent manner. The levels of lgl1 protein and LGL1 mRNA expression were decreased in those explants that had inhibited airway branching, compared with the uninhibited controls. Our findings suggest that lgl1 plays an important role in fetal airway branching morphogenesis.

Animals↗