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The Growth Factor Midkine Is Modulated by Both Glucocorticoid and Retinoid in Fetal Lung Development

McGill University-Montreal Children's Hospital Research Institute, Departments of Human Genetics and Pediatrics, and Montreal Genome Centre, McGill University Health Centre, Montreal, Quebec, Canada; Departments of Pediatrics, Molecular Biology, and Pharmacology, Washington University in St. Louis School of Medicine, St. Louis, Missouri; Lung Biology Research, Research Institute, The Hospital for Sick Children, Toronto; and Departments of Physiology and Pediatrics, University of Toronto, Toronto, Ontario, Canada

Address correspondence to: Feige Kaplan, McGill University-Montreal Children's Hospital Research Institute, 4060 St Catherine St West Rm 236, Montreal, QC H3Z2Z3

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 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.

Abbreviations: extracellular matrix, ECM • glucocorticoids, GC • GC receptor, GR • midkine, MK • retinoids, RA

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