Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-09, Vol.63 (17), p.5320-5328
• Main Authors: WENBIN MA, TESSAROLLO, Lino, PACK, Svetlana, VORTMEYER, Alexander O, CHUANFA GUO, ZBAR, Berton, SCHMIDT, Laura S, HONG, Seung-Beom, BABA, Masaya, SOUTHON, Eileen, BACK, Timothy C, SPENCE, Sally, LOBE, Corrinne G, SHARMA, Nirmala, MAHER, Gregory W
• Format: Article
• Language: English
• Subjects: Actins - genetics; Alleles; Animals; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Disease Models, Animal; DNA Nucleotidyltransferases - genetics; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Silencing; Hemangioma - blood supply; Hemangioma - genetics; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms, Experimental - blood supply; Liver Neoplasms, Experimental - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular and cellular biology; Neovascularization, Pathologic - genetics; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Promoter Regions, Genetic; Recombinases; Recombination, Genetic; Spermatogenesis - genetics; Transcription Factors; Up-Regulation; von Hippel-Lindau Disease - genetics
• ISSN: 0008-5472; 1538-7445

von Hippel-Lindau (VHL) disease is a multisystem inherited cancer syndrome characterized by the development of highly vascular tumors including hemangioblastomas of the retina and central nervous system, pheochromocytomas, and clear cell renal carcinoma, which result from somatic inactivation of the wild-type VHL allele in cells harboring a germ-line VHL mutation. Homozygous inactivation of the VHL gene in mice resulted in embryonic lethality. To produce a mouse model that closely mimics human VHL disease and avoids embryonic lethality, we used Cre/lox site-specific recombination technology. We generated mice carrying conditional VHL alleles and a cre transgene under the control of the human beta-actin promoter, which directs cre expression in a mosaic pattern in multiple organs. VHL(f/d)/Cre mice developed multiple, hepatic hemangiomas that led to premature death, as well as angiectasis and angiogenesis in multiple organs. Interestingly, testes of male VHL(f/d)/Cre mice were unusually small with severely reduced sperm count resulting in infertility. Loss of pVHL function in this VHL conditional knockout mouse model results in an extensive abnormal vascular phenotype in multiple mouse organs, which will provide a useful animal model for testing potential antiangiogenic therapies for VHL disease treatment. Importantly, the phenotypic defects in sperm development observed in these mice support a novel role for VHL in spermatogenesis. This VHL conditional knockout mouse model will provide an in vivo system for studying the functional requirement of the VHL gene in reproductive biology.