Pathogenesis of persistent hyperplastic primary vitreous in mice lacking the Arf tumor suppressor gene

Amy C. Martin, J. Derek Thornton, Jiewiu Liu, Xiao Fei Wang, Jian Zuo, Monica Jablonski, Edward Chaum, Frederique Zindy, Stephen X. Skapek

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

PURPOSE. Persistent hyperplastic primary vitreous (PHPV) is an idiopathic developmental eye disease associated with failed involution of the hyaloid vasculature. The present work addressed the pathogenesis of PHPV in a mouse model that replicates many aspects of the human disease. METHODS. Ophthalmoscopic and histologic analyses documented pathologic processes in eyes of mice lacking the Arf gene compared with Ink4a-deficient and wild-type control animals. Immunohistochemical staining, in situ hybridization, and RT-PCR demonstrated the expression of relevant gene products. Arf gene expression was determined by in situ hybridization using wholemounts of wild-type mouse eyes and by immunofluorescence staining for green fluorescent protein (GFP) in Arf+/GFP heterozygous knock-in mouse eyes. RESULTS. Abnormalities in Arf-/- mice mimicked those found in patients with severe PHPV. The mice had microphthalmia; flbrovascular, retrolental tissue containing retinal pigment epithelial cells and remnants of the hyaloid vascular system; posterior lens capsule destruction with lens degeneration and opacity; and severe retinal dysplasia and detachment. Eyes of mice lacking the overlapping Ink4a gene were normal. Arf was selectively expressed in perivascular cells within the vitreous of the postnatal eye. Cells composing the retrolental mass in Arf-/- mice expressed the Arf promoter. The remnant hyaloid vessels expressed Flk-1. Its ligand, vascular endothelial growth factor (Vegf), was expressed in the retrolental tissue and the adjacent dysplastic neuroretina. CONCLUSIONS. Arf-/- mice have features that accurately mimic severe PHPV. In the HVS, Arf expression in perivascular cells may block their accumulation or repress Vegf expression to promote HVS involution and prevent PHPV.

Original languageEnglish (US)
Pages (from-to)3387-3396
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume45
Issue number10
DOIs
StatePublished - Oct 1 2004

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Persistent Hyperplastic Primary Vitreous
Tumor Suppressor Genes
Green Fluorescent Proteins
Vascular Endothelial Growth Factor A
In Situ Hybridization
Retinal Dysplasia
Posterior Capsule of the Lens
Overlapping Genes
Staining and Labeling
Microphthalmos
Gene Expression
Wild Animals
Retinal Pigments
Eye Diseases
Retinal Detachment
Pathologic Processes
Cataract
Fluorescent Antibody Technique
Blood Vessels
Epithelial Cells

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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Pathogenesis of persistent hyperplastic primary vitreous in mice lacking the Arf tumor suppressor gene. / Martin, Amy C.; Thornton, J. Derek; Liu, Jiewiu; Wang, Xiao Fei; Zuo, Jian; Jablonski, Monica; Chaum, Edward; Zindy, Frederique; Skapek, Stephen X.

In: Investigative Ophthalmology and Visual Science, Vol. 45, No. 10, 01.10.2004, p. 3387-3396.

Research output: Contribution to journalArticle

Martin, Amy C. ; Thornton, J. Derek ; Liu, Jiewiu ; Wang, Xiao Fei ; Zuo, Jian ; Jablonski, Monica ; Chaum, Edward ; Zindy, Frederique ; Skapek, Stephen X. / Pathogenesis of persistent hyperplastic primary vitreous in mice lacking the Arf tumor suppressor gene. In: Investigative Ophthalmology and Visual Science. 2004 ; Vol. 45, No. 10. pp. 3387-3396.
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T1 - Pathogenesis of persistent hyperplastic primary vitreous in mice lacking the Arf tumor suppressor gene

AU - Martin, Amy C.

AU - Thornton, J. Derek

AU - Liu, Jiewiu

AU - Wang, Xiao Fei

AU - Zuo, Jian

AU - Jablonski, Monica

AU - Chaum, Edward

AU - Zindy, Frederique

AU - Skapek, Stephen X.

PY - 2004/10/1

Y1 - 2004/10/1

N2 - PURPOSE. Persistent hyperplastic primary vitreous (PHPV) is an idiopathic developmental eye disease associated with failed involution of the hyaloid vasculature. The present work addressed the pathogenesis of PHPV in a mouse model that replicates many aspects of the human disease. METHODS. Ophthalmoscopic and histologic analyses documented pathologic processes in eyes of mice lacking the Arf gene compared with Ink4a-deficient and wild-type control animals. Immunohistochemical staining, in situ hybridization, and RT-PCR demonstrated the expression of relevant gene products. Arf gene expression was determined by in situ hybridization using wholemounts of wild-type mouse eyes and by immunofluorescence staining for green fluorescent protein (GFP) in Arf+/GFP heterozygous knock-in mouse eyes. RESULTS. Abnormalities in Arf-/- mice mimicked those found in patients with severe PHPV. The mice had microphthalmia; flbrovascular, retrolental tissue containing retinal pigment epithelial cells and remnants of the hyaloid vascular system; posterior lens capsule destruction with lens degeneration and opacity; and severe retinal dysplasia and detachment. Eyes of mice lacking the overlapping Ink4a gene were normal. Arf was selectively expressed in perivascular cells within the vitreous of the postnatal eye. Cells composing the retrolental mass in Arf-/- mice expressed the Arf promoter. The remnant hyaloid vessels expressed Flk-1. Its ligand, vascular endothelial growth factor (Vegf), was expressed in the retrolental tissue and the adjacent dysplastic neuroretina. CONCLUSIONS. Arf-/- mice have features that accurately mimic severe PHPV. In the HVS, Arf expression in perivascular cells may block their accumulation or repress Vegf expression to promote HVS involution and prevent PHPV.

AB - PURPOSE. Persistent hyperplastic primary vitreous (PHPV) is an idiopathic developmental eye disease associated with failed involution of the hyaloid vasculature. The present work addressed the pathogenesis of PHPV in a mouse model that replicates many aspects of the human disease. METHODS. Ophthalmoscopic and histologic analyses documented pathologic processes in eyes of mice lacking the Arf gene compared with Ink4a-deficient and wild-type control animals. Immunohistochemical staining, in situ hybridization, and RT-PCR demonstrated the expression of relevant gene products. Arf gene expression was determined by in situ hybridization using wholemounts of wild-type mouse eyes and by immunofluorescence staining for green fluorescent protein (GFP) in Arf+/GFP heterozygous knock-in mouse eyes. RESULTS. Abnormalities in Arf-/- mice mimicked those found in patients with severe PHPV. The mice had microphthalmia; flbrovascular, retrolental tissue containing retinal pigment epithelial cells and remnants of the hyaloid vascular system; posterior lens capsule destruction with lens degeneration and opacity; and severe retinal dysplasia and detachment. Eyes of mice lacking the overlapping Ink4a gene were normal. Arf was selectively expressed in perivascular cells within the vitreous of the postnatal eye. Cells composing the retrolental mass in Arf-/- mice expressed the Arf promoter. The remnant hyaloid vessels expressed Flk-1. Its ligand, vascular endothelial growth factor (Vegf), was expressed in the retrolental tissue and the adjacent dysplastic neuroretina. CONCLUSIONS. Arf-/- mice have features that accurately mimic severe PHPV. In the HVS, Arf expression in perivascular cells may block their accumulation or repress Vegf expression to promote HVS involution and prevent PHPV.

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