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

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 Ϫ͞Ϫ and p53 Ϫ͞Ϫ 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.

Transient expression of theArftumor suppressor during male germ cell and eye development inArf-Crereporter mice

“…During the first week of postnatal development, Arf expression in mural cells is required for involution of the HVS, a process that clears the vitreous and is required to ensure normal vision. In Arf-null mice, the vitreal HVS persists and is accompanied by an abnormal proliferation of perivascular cells that form a funnelshaped retrolental mass that ultimately disrupts the posterior lens and retina, leading to blindness (6).…”

“…This finding suggests that although the penetrance of Arf-Cre expression in cells within the vitreal HVS was not complete, sufficient numbers of Arf-null cells induced functional ocular damage in 8 of the 10 eyes that were individually examined. Typical ocular lesions in Arf-null animals are characterized by aberrant retinal folding, the appearance of a dysplastic neuroretina detached from pigmented epithelium, and the emergence of a fibrotic retrolental mass containing pigmented cells that erodes the posterior lens; these abnormalities collectively contribute to gross anatomic micro-ophthalmia (6,22). Interestingly, 1 animal (Mouse #4 in Table 2) was completely blind in 1 eye but had normal vision in the other.…”

Myc pathways provoking cell suicide and cancer

“…The longer latency required for tumor appearance and the altered spectrum of malignancies in Arf-deficient mice suggested that Arf may also operate in a p53-independent manner (Kamijo et al, 1999). Indeed, Arf has been shown to regulate angiogenesis of the eye (McKeller et al, 2002), inhibit ribosomal RNA processing (Sugimoto et al, 2003) and NF-kB signaling (Rocha et al, 2003) in a p53-independent manner, and can, when overexpressed in Arf-Mdm2-p53 triply deficient cells, cause cell cycle arrest .…”

Small mitochondrial Arf (smArf) protein corrects p53-independent developmental defects of Arf tumor suppressor-deficient mice

“…Arf-null mice exhibit late embryonal and early postnatal persistence of the hyaloid vasculature in the vitreous of their eyes because of an abnormal proliferation of mural mesenchymal cells that envelop the hyaloid capillary vascular endothelium (32). In wild-type mice, the hyaloid vasculature normally undergoes regression in the first weeks after birth to leave a clear avascular vitreous.…”