Background: Although there is strong evidence that genetic factors play a pathogenic role in congenital diaphragmatic hernia (CDH), few causal genes have been identified in humans. A number of studies, essentially in animal models, have suggested that disruption of the retinoid signaling pathway plays a major role in the pathogenesis of CDH. Our hypothesis is that human fetal skin fibroblasts express some metabolic and molecular actors of the retinoid pathway and that they offer convenient cellular material for investigating the molecular retinoid pathway defects associated with CDH.
Methods: We first established the expression of receptors, enzymes and binding proteins involved in the retinoic acid (RA) pathway in non-CDH fetal skin fibroblasts using RT-PCR and immunocytochemistry approaches. We then studied the expression of these genes in skin fibroblasts from seven fetuses with isolated and nonisolated CDH.
Results: Fetal skin fibroblasts expressed enzymes involved in RA metabolism as well as nuclear receptors for signal transduction. Basal levels of retinoic acid receptor, retinaldehyde dehydrogenase 2, and CYP26 (cytochrome P450 RAI) expression were altered in two of seven fetuses. Interestingly, these genes were previously described as abnormally expressed in CDH physiopathology.
Conclusion: Our results suggest that human fetal skin fibroblasts could be useful for studying retinoid signaling pathway disruption in the context of CDH. Our proposal is strengthened by the fact that we identified CDH fetuses for which molecular and metabolic actors of the retinoid pathway were not detected.
Copyright 2010 Wiley-Liss, Inc.