TY - JOUR
T1 - Pancreas-specific deletion of Prox1 affects development and disrupts homeostasis of the exocrine pancreas
AU - Westmoreland, Joby J.
AU - Kilic, Gamze
AU - Sartain, Caroline
AU - Sirma, Sema
AU - Blain, Jennifer
AU - Rehg, Jerold
AU - Harvey, Natasha
AU - Sosa-Pineda, Beatriz
N1 - Funding Information:
Funding Supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health ( 5 R01DK060542 ), and American Lebanese Syrian Associated Charities.
PY - 2012/4
Y1 - 2012/4
N2 - Background & Aims: The exocrine portion of the pancreas functions in digestion and preserves pancreatic homeostasis. Learning how this tissue forms during embryogenesis could improve our understanding of human pancreatic diseases. Expression of the homeobox gene Prox1 in the exocrine pancreas changes throughout development in mice. We investigated the role of Prox1 in development of the exocrine pancreas in mice. Methods: Mice with pancreas-specific deletion of Prox1 (Prox1ΔPanc) were generated and their pancreatic tissues were analyzed using immunohistochemistry, transmission electron microscopy, histologic techniques, quantitative real-time polymerase chain reaction, immunoblotting, and morphometric analysis. Results: Loss of Prox1 from the pancreas led to multiple exocrine alterations, most notably premature acinar cell differentiation, increased ductal cell proliferation, altered duct morphogenesis, and imbalanced expression of claudin proteins. Prox1ΔPanc mice also had some minor alterations in islet cells, but beta-cell development was not affected. The exocrine congenital defects of Prox1ΔPanc pancreata appeared to initiate a gradual process of deterioration that resulted in extensive loss of acinar cells, lipomatosis, and damage to ductal tissue in adult mice. Conclusions: Pancreas-specific deletion of Prox1 causes premature differentiation of acinar cells and poor elongation of epithelial branches; these defects indicate that Prox1 controls the expansion of tip progenitors in the early developing pancreas. During later stages of embryogenesis, Prox1 appears to regulate duct cell proliferation and morphogenesis. These findings identify Prox1 as an important regulator of pancreatic exocrine development.
AB - Background & Aims: The exocrine portion of the pancreas functions in digestion and preserves pancreatic homeostasis. Learning how this tissue forms during embryogenesis could improve our understanding of human pancreatic diseases. Expression of the homeobox gene Prox1 in the exocrine pancreas changes throughout development in mice. We investigated the role of Prox1 in development of the exocrine pancreas in mice. Methods: Mice with pancreas-specific deletion of Prox1 (Prox1ΔPanc) were generated and their pancreatic tissues were analyzed using immunohistochemistry, transmission electron microscopy, histologic techniques, quantitative real-time polymerase chain reaction, immunoblotting, and morphometric analysis. Results: Loss of Prox1 from the pancreas led to multiple exocrine alterations, most notably premature acinar cell differentiation, increased ductal cell proliferation, altered duct morphogenesis, and imbalanced expression of claudin proteins. Prox1ΔPanc mice also had some minor alterations in islet cells, but beta-cell development was not affected. The exocrine congenital defects of Prox1ΔPanc pancreata appeared to initiate a gradual process of deterioration that resulted in extensive loss of acinar cells, lipomatosis, and damage to ductal tissue in adult mice. Conclusions: Pancreas-specific deletion of Prox1 causes premature differentiation of acinar cells and poor elongation of epithelial branches; these defects indicate that Prox1 controls the expansion of tip progenitors in the early developing pancreas. During later stages of embryogenesis, Prox1 appears to regulate duct cell proliferation and morphogenesis. These findings identify Prox1 as an important regulator of pancreatic exocrine development.
KW - Mouse Model
KW - Organogenesis
KW - Regulation
KW - Transcription
UR - http://www.scopus.com/inward/record.url?scp=84859439941&partnerID=8YFLogxK
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U2 - 10.1053/j.gastro.2011.12.007
DO - 10.1053/j.gastro.2011.12.007
M3 - Article
C2 - 22178591
AN - SCOPUS:84859439941
SN - 0016-5085
VL - 142
SP - 999-1009.e6
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -