Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas
Akihisa Fukuda, … , Christopher V.E. Wright, Tsutomu Chiba
Akihisa Fukuda, … , Christopher V.E. Wright, Tsutomu Chiba
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1484-1493. https://doi.org/10.1172/JCI27704.
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Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas

Abstract

Ectopic pancreas is a developmental anomaly occasionally found in humans. Hes1, a main effector of Notch signaling, regulates the fate and differentiation of many cell types during development. To gain insights into the role of the Notch pathway in pancreatic fate determination, we combined the use of Hes1-knockout mice and lineage tracing employing the Cre/loxP system to specifically mark pancreatic precursor cells and their progeny in Ptf1a-cre and Rosa26 reporter mice. We show that inactivation of Hes1 induces misexpression of Ptf1a in discrete regions of the primitive stomach and duodenum and throughout the common bile duct. All ectopic Ptf1a-expressing cells were reprogrammed, or transcommitted, to multipotent pancreatic progenitor status and subsequently differentiated into mature pancreatic exocrine, endocrine, and duct cells. This process recapitulated normal pancreatogenesis in terms of morphological and genetic features. Furthermore, analysis of Hes1/Ptf1a double mutants revealed that ectopic Ptf1a-cre lineage–labeled cells adopted the fate of region-appropriate gut epithelium or endocrine cells similarly to Ptf1a-inactivated cells in the native pancreatic buds. Our data demonstrate that the Hes1-mediated Notch pathway is required for region-appropriate specification of pancreas in the developing foregut endoderm through regulation of Ptf1a expression, providing novel insight into the pathogenesis of ectopic pancreas development in a mouse model.

Authors

Akihisa Fukuda, Yoshiya Kawaguchi, Kenichiro Furuyama, Sota Kodama, Masashi Horiguchi, Takeshi Kuhara, Masayuki Koizumi, Daniel F. Boyer, Koji Fujimoto, Ryuichiro Doi, Ryoichiro Kageyama, Christopher V.E. Wright, Tsutomu Chiba

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Figure 3

Ectopic pancreas formation in the CBD and MDP in Hes1–/– Ptf1acre/wt ROSA26r mice.

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Ectopic pancreas formation in the CBD and MDP in Hes1...
Macroscopic and microscopic views of the X-gal–stained CBD at E17.5 show that the Ptf1a lineage–negative normal CBD in Hes1WT/WT mice (arrows in A) was replaced by Ptf1a lineage–labeled pancreatic tissue in Hes1-null mice (arrows in B and D). Note that the duodenum is light blue because of endogenous β-galactosidase activity. The converted pancreatic tissue extended from the site where the cystic duct would have joined the CBD to the junction with the duodenum (B). Note that the native ventral pancreas (arrow in C) and rare cells just beside the CBD (arrowhead in C) were Ptf1a lineage labeled in Hes1WT/WT mice. The DBA-positive CBD epithelium at the MDP (E) was replaced by DBA-negative, Ptf1a lineage–labeled pancreatic tissue in Hes1-null mice (F). Neither amylase- nor insulin-producing cells were present in the CBD in Hes1WT/WT mice (G). (H) Double immunostaining showed that the ectopic pancreatic tissue at the MDP was positive for amylase and insulin in Hes1-null mice (note that F and H are adjacent sections). The normal structure of the MDP is shown (I). (J) Ectopic pancreatic tissue penetrated the duodenal wall at the MDP, shown by α-SMA immunostaining. Cdx2 immunostaining showed that Cdx2 was not expressed in the biliary epithelium (arrow in K) and the ectopic pancreas (arrow in L) but was expressed in the duodenal epithelium (K and L). Papilla, MDP; VP, ventral pancreas. Scale bars: 50 μm.