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At metamorphosis the Xenopus laevis tadpoleexocrine pancreas remodels in two stages. At the climax of metamorphosis thyroid hormone (TH) induces dedifferentiation of the entire exocrine pancreas to a progenitor state. The organ shrinks to 20% of its size, and approximately 40% of its cells die. The acinar cells lose their zymogen granules and approximately 75% of their RNA. The mRNAs that encode exocrine-specific proteins (including the transcription factor Ptf1a) undergo almost complete extinction at climax, whereas PDX-1, Notch-1, and Hes-1, genes implicated in differentiation of the progenitor cells, are activated. At the end of spontaneous metamorphosis when the endogenous TH has reached a low level, the pancreas begins to redifferentiate. Exogenous TH induces the dedifferentiation phase but not the redifferentation phase. The tadpolepancreas lacks the mature ductal system that is found in adult vertebrate pancreases, including the frog. Exocrine pancreases of transgenic tadpoles expressing a dominant negative form of the TH receptor controlled by the elastase promoter are resistant to TH. They do not shrink when subjected to TH. Their acinar cells do not dedifferentiate at climax, nor do they down-regulate exocrine-specific genes or activate Notch-1 and Hes-1. Even 2 months after metamorphosis these frogs have not developed a mature ductal system and the acinar cells are abnormally arranged. The TH-dependent dedifferentiation of the tadpole acinar cells at climax is a necessary step in the formation of a mature frog pancreas.
Fig. 2. Change in gene expression in the exocrine pancreas during metamorphosis. (A–D and I–L) In situ hybridization with amylase (A–D) and Ptf1a (I–L) probes. Every mRNA encoding a “terminally differentiated†exocrine protein that we have tested is extinguished at metamorphic climax (NF62) to the same extent as these 2 mRNAs (see discussion). (E–H) Although amylase mRNA is extinguished at climax, amylase protein was still detected by immunohistochemistry, confirming the dedifferentiation stages of previously differentiated exocrine cells. (Scale bar: 40 μm.)
Fig. 3. Change in gene expression in the exocrine pancreas during metamorphosis. (A–C) In situ hybridization with PDX-1 probes. PDX-1 is expressed exclusively in islet cells in the tadpole (A) and frog pancreases (C), and at climax expression is extended to the dedifferentiated exocrine cells (B). (D–I) Notch-1 (D–F) and Hes-1 (G–I) genes are activated at climax, although low level of expression of Notch-1 and Hes-1 has been observed at premetamorphic and adult frogs. (Scale bar: 40 μm.)
Fig. 7. Schematic representation of morphological and gene expression changes in the exocrine pancreas during X. laevis metamorphosis. The adult frog pancreas has all of the types of ducts that have been described for adult vertebrates. Tadpoles lack the intercalated ducts. At the climax of metamorphosis, TH induces dedifferentiation of the exocrine pancreas to a progenitor state that has extinguished the mRNAs encoding terminally differentiated proteins (represented by amylase). PDX-1, Notch-1, and Hes-1 are up-regulated. Late in climaxPtf1a is reactivated followed by the differentiation of acinar and duct cells. Abbreviations: ac-acinar; ld-lobular duct, icd-intercalated duct. Figure is not drawn to scale.
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