Deciphering von hippel-lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations

H. C Jennifer Shen, Asha Adem, Kris Ylaya, Arianne Wilson, Mei He, Dominique Lorang, Stephen M. Hewitt, Klaus Pechhold, David M. Harlan, Irina A. Lubensky, Laura S. Schmidt, W. Marston Linehan, Steven K. Libutti

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Abstract

The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in α-cells or an insulin promoter in b-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated α-cells or β-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.

Original languageEnglish (US)
Article numbere4897
JournalPLoS One
Volume4
Issue number4
DOIs
StatePublished - Apr 2 2009
Externally publishedYes

Fingerprint

pancreas
Cells
Tumors
Pancreas
Population
Pancreatic Diseases
pancreatic diseases
Neurology
cells
Glucagon
mice
lesions (animal)
Stem Cells
stem cells
Insulin
Hemangioblastoma
von Hippel-Lindau Disease
Exocrine Pancreas
promoter regions
Endocrine Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Deciphering von hippel-lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. / Shen, H. C Jennifer; Adem, Asha; Ylaya, Kris; Wilson, Arianne; He, Mei; Lorang, Dominique; Hewitt, Stephen M.; Pechhold, Klaus; Harlan, David M.; Lubensky, Irina A.; Schmidt, Laura S.; Linehan, W. Marston; Libutti, Steven K.

In: PLoS One, Vol. 4, No. 4, e4897, 02.04.2009.

Research output: Contribution to journalArticle

Shen, HCJ, Adem, A, Ylaya, K, Wilson, A, He, M, Lorang, D, Hewitt, SM, Pechhold, K, Harlan, DM, Lubensky, IA, Schmidt, LS, Linehan, WM & Libutti, SK 2009, 'Deciphering von hippel-lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations', PLoS One, vol. 4, no. 4, e4897. https://doi.org/10.1371/journal.pone.0004897
Shen, H. C Jennifer ; Adem, Asha ; Ylaya, Kris ; Wilson, Arianne ; He, Mei ; Lorang, Dominique ; Hewitt, Stephen M. ; Pechhold, Klaus ; Harlan, David M. ; Lubensky, Irina A. ; Schmidt, Laura S. ; Linehan, W. Marston ; Libutti, Steven K. / Deciphering von hippel-lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. In: PLoS One. 2009 ; Vol. 4, No. 4.
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abstract = "The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75{\%} of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in α-cells or an insulin promoter in b-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated α-cells or β-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.",
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AU - Wilson, Arianne

AU - He, Mei

AU - Lorang, Dominique

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