The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development

doi:10.1073/pnas.052484199

The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development

Departments of ^*Hematology/Oncology, ^†Developmental Neurobiology, and ^‡Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 31, 2001 (received for review September 13, 2001)

Abstract

A key tumor suppressor mechanism that is disrupted frequently in human cancer involves the ARF and p53 genes. In mouse fibroblasts, the Arf gene product responds to abnormal mitogenic signals to activate p53 and trigger either cell cycle arrest or apoptosis. Recent evidence indicates that Arf also has p53-independent functions that may contribute to its tumor suppressor activity. Using Arf ^−/− and p53 ^−/− mice, we have discovered a p53-independent requirement for Arf in the developmental regression of the hyaloid vascular system (HVS) in the mouse eye. Arf is expressed in the vitreous of the eye and is induced before HVS regression in the first postnatal week. In the absence of Arf, failed HVS regression causes a pathological process that resembles persistent hyperplastic primary vitreous, a developmental human eye disease thought to have a genetic basis. These findings demonstrate an essential and unexpected role for Arf during mouse eye development, provide insights into the potential genetic basis for persistent hyperplastic primary vitreous, and indicate that Arf regulates vascular regression in a p53-independent manner. The latter finding raises the possibility that Arf may function as a tumor suppressor at least in part by regulating tumor angiogenesis.

Footnotes

↵ § To whom reprint requests should be addressed at: Department of Hematology/Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Room D1034, Memphis, TN 38105. E-mail: Steve.Skapek{at}stjude.org.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

GAPDH,

glyceraldehyde-3-phosphate dehydrogenase;

HVS,

hyaloid vascular system;

PHPV,

persistent hyperplastic primary vitreous;

H&E,

hematoxylin/eosin;

VHP,

vasa hyaloidea propria;

HA,

hyaloid artery;

Pn,

postnatal day n;

RT,

reverse transcriptase;

VEGF,

vascular endothelial growth factor