All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas.
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.
Tulachan
Sidhartha Singh
SS
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Doi
Ryuichiro
R
Kawaguchi
Yoshiya
Y
Tsuji
Shoichiro
S
Nakajima
Sanae
S
Masui
Toshihiko
T
Koizumi
Masayuki
M
Toyoda
Eiji
E
Mori
Tomohiko
T
Ito
Daisuke
D
Kami
Kazuhiro
K
Fujimoto
Koji
K
Imamura
Masayuki
M
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
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