TY - JOUR
T1 - Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signalling
AU - Arregi, Igor
AU - Climent, Maria
AU - Iliev, Dobromir
AU - Strasser, Jürgen
AU - Gouignard, Nadège
AU - Johansson, Jenny K
AU - Singh, Tania
AU - Mazur, Magdalena
AU - Semb, Henrik
AU - Artner, Isabella
AU - Minichiello, Liliana
AU - Pera, Edgar M
PY - 2016/12
Y1 - 2016/12
N2 - Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagonβ and insulinβ cells. During the secondary transition, the reduction of Neurogenin3β endocrine progenitors in the mutant dorsal pancreas accounted for fewer β-and α-cells. Changes in the expression of β-and α-cellspecific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal andepithelialRdh10forpancreogenesisandthefirstwaveofendocrinecell differentiation.Wefurther propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source ofRAsignals in the second wave of endocrine cell differentiation.
AB - Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagonβ and insulinβ cells. During the secondary transition, the reduction of Neurogenin3β endocrine progenitors in the mutant dorsal pancreas accounted for fewer β-and α-cells. Changes in the expression of β-and α-cellspecific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal andepithelialRdh10forpancreogenesisandthefirstwaveofendocrinecell differentiation.Wefurther propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source ofRAsignals in the second wave of endocrine cell differentiation.
U2 - 10.1210/en.2016-1745
DO - 10.1210/en.2016-1745
M3 - Journal article
C2 - 27740873
SN - 0013-7227
VL - 157
SP - 4615
EP - 4631
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 12
M1 - en20161745
ER -