Deciphering von Hippel-Lindau (VHL/Vhl)-Associated Pancreatic Manifestations by Inactivating Vhl in Specific Pancreatic Cell Populations

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 β-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.

Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

“…In view of abundant evidence linking certain types of cysts to defects in primary cilia, it has been suggested that the microtubule stabilization function of VHL is key to its role in suppressing cysts (66). Several mouse models in which the VHL gene has been inactivated develop various cysts (although not SCAs) (67)(68)(69)(70), suggesting fertile avenues for future research on this topic.…”

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

“…39 In our studies, the b-cell-specific VHL-knockout mice, in which cre-mediated VHL deletion was under the control of the RIP, did not demonstrate any evidence of tumor development, similar to a study by Cantley et al 27 In addition, in this study, mice in which VHL was deleted under the control of the Pdx-1 promoter (Tg (Pdx1-cre) 1Herr) was used, which also demonstrated a glucose intolerant phenotype due to impaired insulin secretion. However, another study by Shen et al 40 showed that mice with Pdx-1-driven VHL deletion in a different genetic background (Tg (Pdx1-cre) 89.1Dam) resulted in tumor development and early mortality.…”

Animal models of spontaneous pancreatic neuroendocrine tumors

“…Global homozygous deletion of Vhl in mice results in embryonic death; global heterozygous Vhl deletion, meanwhile, is not associated with any significant abnormalities even at 15 months (Gnarra et al, 1997). Furthermore, β or α cell-specific homozygous Vhl deletion in mice also does not results in PNETs (Shen et al, 2009b). Specific homozygous Vhl deletion from M A N U S C R I P T…”