Retinoids during the embryonic period act as a mesenchymal inducer in many organs, including kidney, lung, central nervous system, and gut. Retinoic acid (RA) demonstrates insulinotropic effects in adult pancreas, but only a limited study has elucidated its role in pancreatic organogenesis. In this study, we have analyzed the existence of RA-signaling machinery in embryonic pancreas and evaluated its role using in vitro tissue culture experiments. Here we show the presence of endogenous retinaldehyde dehydrogenase 2 (RALDH2), the most effective RA-synthesizing enzyme, RA-binding proteins, and RA receptors (RARs) in embryonic pancreatic tissue. RALDH2 is expressed exclusively in the mesenchyme. Exogenously added all-trans-retinoic acid (atRA) in tissue culture experiments stimulated differentiation of endocrine and duct cells and promoted apoptotic cell death of acinar tissue. Furthermore, we demonstrate that atRA upregulates the PDX-1 expression. Taken together, our data suggest that atRA-mediated mesenchymal/epithelial interactions play an important role in determining the cell fate of epithelial cells via regulation of the PDX-1 gene, leading to the proper formation of the endocrine versus exocrine component during pancreatic organogenesis.
Address correspondence and reprint requests to Ryuichiro Doi, MD, Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, 54 Shogoin, Kawara cho, Sakyoku, Kyoto 606-8507, Japan. E-mail:.
Received for publication 8 June 2002 and accepted in revised form 23 September 2002.
atRA, all-trans retinoic acid; COUP-TF II, chicken ovalbumin upstream promoter transcription factor II; CRABP II, cellular retinoic acid binding protein II; PE, pancreatic epithelia only; PEM, pancreatic epithelia with mesenchyme; RALDH2, retinaldehyde dehydrogenase 2; RA, retinoic acid; RAR, retinoic acid receptor; RARE, retinoic acid responsive element.