This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ma, W. Articles by Schmidt, L. S. Search for Related Content PubMed PubMed Citation Articles by Ma, W. Articles by Schmidt, L. S.

Hepatic Vascular Tumors, Angiectasis in Multiple Organs, and Impaired Spermatogenesis in Mice with Conditional Inactivation of the VHL Gene¹

Laboratory of Immunobiology, Center for Cancer Research [W. M., S-B. H., N. S., G. W. M., B. Z.], Mouse Cancer Genetics Program [L. T., S. S.], Laboratory of Animal Sciences [E. S.], and Basic Research Program [T. C. B., L. S. S.], Science Applications International Corporation-Frederick, Inc., National Cancer Institute Frederick, Frederick, Maryland 21702; Department of Urology, Yokohama City School of Medicine, Yokohama, 236 Japan [M. B.]; Molecular and Cellular Biology Research, Sunnybrook and Women’s College Health Centre, Toronto, Ontario, Canada M4N 3M5 [C. G. L.]; Surgical Neurology Branch, National Institute of Neurologic Disease, Blindness and Stroke, Bethesda, Maryland 20894 [S. P., A. O. V.]; and Department of Epidemiology and Preventive Medicine, University of Maryland at Baltimore, Baltimore, Maryland 21210 [C. G.]

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 ß-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.

This article has been cited by other articles:

				L. Lei, S. Mason, D. Liu, Y. Huang, C. Marks, R. Hickey, I. S. Jovin, M. Pypaert, R. S. Johnson, and F. J. Giordano Hypoxia-Inducible Factor-Dependent Degeneration, Failure, and Malignant Transformation of the Heart in the Absence of the von Hippel-Lindau Protein Mol. Cell. Biol., June 1, 2008; 28(11): 3790 - 3803. [Abstract] [Full Text] [PDF]

				Y. A. Minamishima, J. Moslehi, N. Bardeesy, D. Cullen, R. T. Bronson, and W. G. Kaelin Jr Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure Blood, March 15, 2008; 111(6): 3236 - 3244. [Abstract] [Full Text] [PDF]

				L. Li, L. Zhang, X. Zhang, Q. Yan, Y. A. Minamishima, A. F. Olumi, M. Mao, S. Bartz, and W. G. Kaelin Jr. Hypoxia-Inducible Factor Linked to Differential Kidney Cancer Risk Seen with Type 2A and Type 2B VHL Mutations Mol. Cell. Biol., August 1, 2007; 27(15): 5381 - 5392. [Abstract] [Full Text] [PDF]

				W. G. Kaelin Jr. The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma Clin. Cancer Res., January 15, 2007; 13(2): 680s - 684s. [Abstract] [Full Text] [PDF]

				D. J. Liepinsh, S. I. Grivennikov, K. D. Klarmann, M. A. Lagarkova, M. S. Drutskaya, S. J. Lockett, L. Tessarollo, M. McAuliffe, J. R. Keller, D. V. Kuprash, et al. Novel Lymphotoxin Alpha (LT{alpha}) Knockout Mice with Unperturbed Tumor Necrosis Factor Expression: Reassessing LT{alpha} Biological Functions. Mol. Cell. Biol., June 1, 2006; 26(11): 4214 - 4225. [Abstract] [Full Text] [PDF]

				N. Zanesi, R. Mancini, C. Sevignani, A. Vecchione, M. Kaou, M. Valtieri, G. A. Calin, Y. Pekarsky, J. R. Gnarra, C. M. Croce, et al. Lung Cancer Susceptibility in Fhit-Deficient Mice Is Increased by Vhl Haploinsufficiency Cancer Res., August 1, 2005; 65(15): 6576 - 6582. [Abstract] [Full Text] [PDF]

				E. B. Rankin, D. F. Higgins, J. A. Walisser, R. S. Johnson, C. A. Bradfield, and V. H. Haase Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice Mol. Cell. Biol., April 15, 2005; 25(8): 3163 - 3172. [Abstract] [Full Text] [PDF]

				B. I. Rini and E. J. Small Biology and Clinical Development of Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma J. Clin. Oncol., February 10, 2005; 23(5): 1028 - 1043. [Abstract] [Full Text] [PDF]

				C. Graveel, Y. Su, J. Koeman, L.-M. Wang, L. Tessarollo, M. Fiscella, C. Birchmeier, P. Swiatek, R. Bronson, and G. Vande Woude Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele PNAS, December 7, 2004; 101(49): 17198 - 17203. [Abstract] [Full Text] [PDF]

				W. K. Rathmell, M. M. Hickey, N. A. Bezman, C. A. Chmielecki, N. C. Carraway, and M. C. Simon In vitro and In vivo Models Analyzing von Hippel-Lindau Disease-Specific Mutations Cancer Res., December 1, 2004; 64(23): 8595 - 8603. [Abstract] [Full Text] [PDF]

				S. Richard, R. Lidereau, S. Giraud, and on behalf of the French inherited kidney tumours c The growing family of hereditary renal cell carcinoma Nephrol. Dial. Transplant., December 1, 2004; 19(12): 2954 - 2958. [Full Text] [PDF]

				V. Coppola, C. A. Barrick, E. A. Southon, A. Celeste, K. Wang, B. Chen, E.-B. Haddad, J. Yin, A. Nussenzweig, A. Subramaniam, et al. Ablation of TrkA function in the immune system causes B cell abnormalities Development, October 15, 2004; 131(20): 5185 - 5195. [Abstract] [Full Text] [PDF]

				W. G. Kaelin Jr. The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer Clin. Cancer Res., September 15, 2004; 10(18): 6290S - 6295S. [Abstract] [Full Text] [PDF]

				R. Depping, S. Hagele, K. F. Wagner, R. J. Wiesner, G. Camenisch, R. H. Wenger, and D. M. Katschinski A Dominant-Negative Isoform of Hypoxia-Inducible Factor-1{alpha} Specifically Expressed in Human Testis Biol Reprod, July 1, 2004; 71(1): 331 - 339. [Abstract] [Full Text] [PDF]

				J. M. Ward and D. E. Devor-Henneman Mouse Models of Human Familial Cancer Syndromes Toxicol Pathol, January 1, 2004; 32(1_suppl): 90 - 98. [Abstract] [PDF]