High frequency of persistent hyperplastic primary vitreous and cataracts in p53-deficient mice

Abstract

In order to investigate whether the p53 gene product plays a role in normal eye development, age matched p53-deficient mice and wild-type controls were sacrificed from day 2 to day 21 after birth. Eyes were paraffin-embedded and sectioned. Serial sections were taken at the level of the tunica vasculosa lentis and the hyaloid artery. The terminal dUTP nick-end labelling technique (TUNEL) was used to detect the number of cells displaying DNA fragmentation within these structures. Eyes were also prepared for scanning electron microscopy and resin embedded for semi-thin sections. Adult wild-type mice and p53-deficient mice were examined ophthalmoscopically in vivo. Ophthalmoscopical examination of mice completely deficient in p53 revealed them to be normal except for the persistence of the hyaloid vasculature, a structure that normally regresses during eye development. In adult animals there was also a high frequency of cataracts. Using morphological assessment and TUNEL we could show that in normal mice, regression of the primary vitreous, which includes the hyaloid artery, the vasa hyaloidea propria as well as the tunica vasculosa lentis, occurs via apoptotic cell death within 5 ± 6 weeks after birth. The number of TUNEL-positive cells within these structures was significantly reduced in the p53-deficient mice in which parts of the hyaloid vasculature persisted and developed into a fibro-vascular retrolental plaque analogous to persistent hyperplastic primary vitreous (PHPV) described in humans. As in humans, PHPV in mice resulted in the development of cataracts. We have identified a role for p53-dependent apoptosis in the regression of the hyaloid vasculature and tunica vasculosa lentis. Our results provide further evidence for the importance of p53 in normal development and provide the first detailed evidence of its role in postnatal development in remodelling the developing eye.

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

“…However, we occasionally observed several layers of retrolental cells in p53 Ϫ͞Ϫ eyes (Fig. 5b), a finding that is consistent with slowed or incomplete HVS regression in some mice (34,35). Importantly, we have not observed lens capsule disruption (Fig.…”

“…HVS regression involves apoptosis in endothelial cells (31,34) and pericytes (41). This apoptosis is at least partially p53-dependent because HVS regression is slowed or incomplete in inbred p53 Ϫ͞Ϫ BALB͞c (34) and C57BL͞6 (35) mice.…”

Role of endothelial cell apoptosis in regulation of skeletal muscle angiogenesis during high and low salt intake

“…Recently, it was demonstrated that retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy is markedly attenuated in Bcl-2Ϫ/Ϫ mice (45). Pathological angiogenesis, such as the persistence of fetal ocular vasculature, can also be observed in mice deficient in proapoptotic proteins, Bax, Bak (22), and P53 (37). In light of this and other evidence, the inhibition of endothelial survival factors, or the activation of endothelial cell death machinery, is considered an attractive strategy in the inhibition of pathological angiogenesis, especially in clinical trials for cancer treatment (39).…”

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

“…36,39,50 All procedures on animals were approved by the local UCL Institute of Ophthalmology Ethics Committee and licensed by the United Kingdom Home Office. Animals were anaesthetised and pupillary mydriasis achieved as previously described.…”