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

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; fibrovascular, 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.

• Authors: Amy C Martin, J Derek Thornton, Jiewiu Liu, XiaoFei Wang, Jian Zuo, Monica M Jablonski, Edward Chaum, Frederique Zindy, Stephen X Skapek
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 45 Issue 10 Pg. 3387-96 (Oct 2004) ISSN: 0146-0404 [Print] United States
• PMID: 15452040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cdkn2a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p16
• Luminescent Proteins
• RNA, Messenger
• Tumor Suppressor Protein p14ARF
• Green Fluorescent Proteins

Topics

• Animals
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Eye Abnormalities (etiology, metabolism, pathology)
• Gene Deletion
• Gene Expression Regulation
• Genotype
• Green Fluorescent Proteins
• Hyperplasia
• Immunohistochemistry
• In Situ Hybridization
• Luminescent Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic (etiology, metabolism, pathology)
• Ophthalmoscopy
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Suppressor Protein p14ARF (genetics, metabolism)
• Vitreous Body (abnormalities, blood supply, pathology)