Deletion of<i>Vhlh</i>in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development

Pfander, David; Kobayashi, Tatsuya; Knight, Melissa C.; Zelzer, Elazar; Chan, Denise A.; Olsen, Bjørn R.; Giaccia, Amato J.; Johnson, Randall S.; Haase, Volker H.; Schipani, Ernestina

doi:10.1242/dev.01138

Cited by 124 publications

(157 citation statements)

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“…For example, tissuespecific inactivation of pVHL in neuro-epithelial progenitor cells resulted in abnormal neuronal differentiation and embryonic lethality during late gestation (VH Haase, unpublished data), and chondrocyte-specific inactivation of pVHL in the growth plate caused stunted bone growth, most likely a consequence of a HIF-dependent increase in cell cycle inhibitor p57 kip2 . 69 In contrast, HIF-1a inactivation in chondrocytes resulted in a lack of p57 kip2 -mediated growth arrest, followed by massive apoptosis. 70 …”

Section: Pvhl During Embryonic Developmentmentioning

confidence: 99%

“…Connective tissue Wang et al 92 OC (osteocalcin) Osteoblasts Bone modeling is increased within the first week of life but appears to decline at latter stages of development; extremely dense, heavily vascularized long bones; progressively increased vessel numbers with age; trabecular separation reduced; no detectable changes in calvarial bone morphology; upregulation of HIF-1 and HIF-2 and VEGF, serum level of VEGF was not elevated; conversely, inactivation of HIF-1a in the osteoblast produced the reverse phenotype, that is, thinner and less vascularized bones Pfander et al 69 ColII (collagen II) Growth plate/ chondrocytes…”

Section: Albuminmentioning

confidence: 99%

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The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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Section: Pvhl During Embryonic Developmentmentioning

confidence: 99%

Section: Albuminmentioning

confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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“…Mice lacking pVHL in cartilage are viable, but grow more slowly than the wild type and develop a severe form of dwarfism. Chondrocyte proliferation within the VHL null growth plates is reduced and atypical large cells are present in the resting zone [21].…”

Section: Regulation Of the Oxemic Response By Phd And Hif Proteinsmentioning

confidence: 99%

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

Shapiro¹,

Srinivas²

2007

Bone

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The goal of this review is to examine some of the metabolic features of the maturing chondrocyte within the epiphyseal growth plate. The energy status of the tissue is examined in light of the energy needs of the tissue and the availability of oxygen. The role of HIF, PHD's and other proteins concerned with transduction of the oxemic response is considered and related to chondrocyte survival in a complex extracellular matrix.

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“…VHL inactivation resulted in defects in spermatogenesis, thymus cell survival and bone development due to reduced cell proliferation and/ or increased cell death. [13][14][15] Contrary to expectation, VHL-inactivation did not increase cell proliferation in somatic and germ cells. Teratomas derived from VHL null embryonic stem (ES) cells displayed a highly vascular phenotype but showed severe reduction of tumor volume compared with heterozygous null ES cells.…”

mentioning

confidence: 88%

Vascular defects and liver damage by the acute inactivation of the VHL gene during mouse embryogenesis

Hong

Furihata

et al. 2006

Laboratory Investigation

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Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene leads to the development of central nervous system hemangioblastomas, pheochromocytomas and renal cell carcinomas. The biological role of the VHL gene during development is poorly understood because of early lethality of VHL-null embryos. To overcome early embryo lethality observed in the conventional knockout mouse, we introduced a tamoxifen-inducible Cre (CreER TM ) transgene for the stage specific inactivation of the VHL gene. Acute tamoxifen-induced inactivation of the VHL gene at E10.5 resulted in embryonic lethality between E14.5 and E15.0 with extensive hemorrhage and necrosis, while littermate controls showed normal development. Examination of the VHL-inactivated embryos between E10.5 and E14.5 revealed dilated blood vessels, hemorrhage and necrotizing liver damage. Concomitant with severe hemorrhage and abnormal vasculature at E15.0, blood circulation in the yolk sac was impaired in the VHL-inactivated embryos, which may be the cause of embryo death. Placental development looked normal before embryo death (E14.5); however, at E16.5 following embryo death, we observed reduced growth of the placental labyrinthine layer. Inactivation of the VHL gene resulted in hypoxia-inducible factor (HIF)-1a stabilization and induction of its target genes, VEGF and CAIX, in mouse embryonic fibroblasts (MEFs). In addition, we observed lactate overproduction and acidification of culture media by the inactivation of the VHL gene. Thus, by using a novel conditional VHL knockout mouse model, we could show that the VHL gene plays an important role in the developing vasculature and liver during embryogenesis through regulation of HIF-1a and its target genes. This mouse model will be useful for the screening of anti-HIF or anti-VEGF drugs in vivo. Additionally, this acute VHL inactivation system may provide a useful tool for the in vivo study of genes that cause early embryonic lethality.

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Deletion ofVhlhin chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development

Cited by 124 publications

References 59 publications

The VHL tumor suppressor and HIF: insights from genetic studies in mice

The VHL tumor suppressor and HIF: insights from genetic studies in mice

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

Vascular defects and liver damage by the acute inactivation of the VHL gene during mouse embryogenesis

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