Role of PPARs and Retinoid X Receptors in the Regulation of Lung Maturation and Development

Abstract

Understanding lung development has significant importance to public health because of the fact that interruptions in the normal developmental processes can have prominent effects on childhood and adult lung health. It is widely appreciated that the retinoic acid (RA) pathway plays an important role in lung development. Additionally, PPARs are believed to partner with receptors of this pathway and therefore could be considered extensions of retinoic acid function, including during lung development. This review will begin by introducing the relationship between the retinoic acid pathway and PPARs followed by an overview of lung development stages and regulation to conclude with details on PPARs and the retinoic acid pathway as they may relate to lung development.

Figure 1

Retinoic acid and PPARγ signaling are essential at many points during lung development. Lung development occurs in multiple stages (top), each involving critical processes (middle) and multiple regulatory factors. This schematic highlights the timeline for human lung development, though murine lung development occurs in similar stages. It is widely appreciated that retinoic acid signaling has effects on all stages of lung development (bottom). Recently, PPARγ has also been found to be a critical modulator of postnatal lung development. (Adapted from Mariani, T.J. Developmental genetics of the pulmonary system. In: Moody, S.A., Editor, Principles of developmental genetics. Burlington, VT: Academic Press, 2007:932-945. With the permission of Elsevier Inc.)

Figure 2

The generation of conditionally targeted epithelial cell PPARγ deficient mice [85]. We developed a line of mice capable of targeting the airway epithelium by expressing Cre recombinase under the direction of the rat CC10 promoter (top, left). These mice, termed CCtCre, were crossed with the ROSA26 Cre reporter mouse to test the efficiency for recombining loxP sites in vivo which demonstrated β-galactosidase staining limited to the conducting airway epithelium (arrow within inset). We crossed the CCtCre mice with mice homozygous for a PPARγ allele with a pair of loxP sites flanking exon 2 of the gene (top, right) [100], creating mice with PPARγ deficiency limited to the conducting airway epithelium (bottom, left). The conditional targeted genotype was confirmed by identification of gene rearrangement specifically in the lung alone (bottom, right).