Retinoic acid (RA) signaling pathway and CDH candidate genes

Retinoic acid (RA) signaling pathway and CDH candidate genes. Retinol travels to target cells via the blood and is taken up by receptors on the cell surface. Once in the cytoplasm, retinol is converted to retinal by retinol dehydrogenases and then to RA by retinal dehydrogenases, of which RALDH2 is the predominant enzyme. The action of RALDH2 can be inhibited by teratogens, such as nitrofen. Several binding proteins are present in the cytoplasm, including retinol-binding proteins 1 and 2 (RBP1 and RBP2), which bind retinol and retinal, and cellular RA-binding proteins 1 and 2 (CRABP1 and CRABP2). When RA enters the nucleus, it mediates its effects by binding to RA receptors (RARs) and retinoid X receptors (RXRs). RARs and RXRs dimerize and regulate gene expression by binding to short DNA sequences—RA-responsive elements (RAREs) and retinoid X–responsive elements (RXREs)—located in the vicinity of target genes. COUP-TFII expression is upregulated by RA. COUP-TFII can act as a repressor of this pathway by directly sequestering RXR, thereby preventing heterodimerization to RAR and inhibiting gene transcription. This process may be a negative feedback system that precisely balances the transcription of certain genes during diaphragm development. COUP-TFII has been shown to interact physically with FOG2, which, in turn, modulates the transcriptional activity of GATA4, GATA5, and GATA6.

Publication

Genetic Factors in Congenital Diaphragmatic Hernia. (2007) A. M. Holder, et al. Am J Hum Genet. 2007 May;80(5):825-845. Figure: F2. Homo sapiens

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