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The tadpolepancreas has differentiated acinar cells but an underdeveloped ductal system. At the climax of metamorphosis thyroid hormone (TH) induces the tadpole acinar cells to dedifferentiate to a progenitor state. After metamorphosis is complete the exocrine pancreas redifferentiates in the growing frog forming a typical vertebrate pancreas including a complex ductal system. A micro array analysis found that TH up regulates stromelysin 3 (ST3, matrix metalloproteinase 11) in the exocrine pancreas at metamorphic climax. Transgenic tadpoles were prepared with an elastase promoter driving either the ST3 gene or the constitutively active form of Notch (IC). Expression of the transgenes was controlled by the tetracycline system. A few days after either of these transgenes is activated by doxycycline the pancreatic acinar cells turn into duct-like cells. This transdetermination occurs without cell division since both acinar and ductal markers can be visualized transiently in the same cell. We propose that remodeling of the tadpole acinar cells is initiated when ST3 is up regulated by TH. Stromelysin-3 then cleaves and activates Notch.
Fig. 1. Expression of stromelysin-3 (ST3) in the pancreas during metamorphosis. A) ST3 mRNA was measured during spontaneous and induced metamorphosis in Xenopus laevis. ST-
3 mRNA is undetectable during pre and pro-metamorphic period as well as in the adult pancreas. However ST3 expression is induced at the climax of metamorphosis (NF62) when
endogenous TH is the highest. Addition of 10 nM T3 induces ST-3 mRNA. Pro-MM is NF58; pre-MM is NF 54–55; B) Control section of an NF55 tadpolepancreas stained with ST3
antiserum; C) ST3 protein is highly up regulated in the pancreas at NF62. Scale bar=20 μm.
Fig. 2. Induction of ST3 mRNA in pancreas causes a morphological change. A) Two plasmids were used for transgenesis. The pancreas specific elastase promoter drives rtTA.
Expression of ST3 is controlled by the Tet (O) promoter. Premetamorphic transgenic animal were exposed to doxycycline. Histological sections of the pancreas, stained with H and E
demonstrate the morphological changes of the exocrine pancreas with time. B) Acinar cells are compactly arranged in non-induced control NF55 tadpoles. C) Some loss of the acinar
structure is observed after day 2 of exposure; D) more advanced changes after 4 days. E) After 8 days of induction with doxy duct-like structures have replaced acini. Scale bar 20 μm.
Fig. 3. Acinar cells transdifferentiate to duct-like cells in a transgenic pancreas induced to express ST3. (See A of Fig. 2 for the two constructs). The sections are double labeled with
antibodies against carbonic anhydrase-II (CA-2) (green) a specific duct cell marker, and amylase (red) an acinar-specific marker. A) premetamorphic control tadpole, B) control adult
frog. A premetamorphic (NF55) transgenic tadpole was induced with tetracycline for C) 2 days, D) 4 days, and E) 8 days. The dotted square in D is magnified in F and G to
demonstrate that CA-2 and amylase are expressed in the same cells. At 8 days of exposure amylase can no longer be detected, and the total number of cells has decreased. The arrows
indicate cells that express both amylase and carbonic anhydrase. Scale bar 20 μm.
Fig. 4. Induction of activated Notch mRNA in the exocrine tadpolepancreas. A) Transgenic tadpoles were prepared with two constructs designed to express Notch IC under the
control of the exocrine elastase promoter and inducible by doxycycline. Premetamorphic (NF55) transgenic animals were exposed to doxycycline for 8 days. B and C are adjacent
sections. B) H and E section of pancreas showing the morphological changes of acinar cells into duct cells after 8 days of exposure. C) Immunohistochemistry showing unchanged
insulin positive cells (arrow, stained red). D) carbonic anhydrase II (green) that is specific for duct cells and E) amylase (red) that detects an enzyme specific for acinar cells. D and E
are sequential sections. All the duct-like structures seen in B are positive for both antibodies. Scale bar 20 μm.
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