title: All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas.
abstract: 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.
authors.affiliation: Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Sidhartha Singh
authors.initials: SS
authors.lastname: Tulachan
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tsuji
authors.forename: Sanae
authors.initials: S
authors.lastname: Nakajima
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Masui
authors.forename: Masayuki
authors.initials: M
authors.lastname: Koizumi
authors.forename: Eiji
authors.initials: E
authors.lastname: Toyoda
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Mori
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kami
authors.forename: Koji
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Imamura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D046508:Culture Techniques / Q000379:methods; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D004703:Endocrine System / Q000196:embryology*; D004848:Epithelium / Q000196:embryology; D005260:Female; D005782:Gels; D018398:Homeodomain Proteins; D008297:Male; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008854:Microscopy, Electron; D010183:Pancreatic Ducts / Q000196:embryology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012176:Retinoids / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
chemical_list: D005782:Gels; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012176:Retinoids; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein; C084010:pancreatic and duodenal homeobox 1 protein; D014212:Tretinoin