Arf-dependent regulation of Pdgf signaling in perivascular cells in the developing mouse eye

We have established that the Arf tumor suppressor gene regulates mural cell biology in the hyaloid vascular system (HVS) of the developing eye. In the absence of Arf, perivascular cells accumulate within the HVS and prevent its involution. We now demonstrate that mural cell accumulation evident at embryonic day (E) 13.5 in Arf^-/- mice was driven by excess proliferation at E12.5, when Arf expression was detectable in vitreous pericyte-like cells. Their expression of Arf overlapped with Pdgf receptor β (Pdgfrβ), which is essential for pericyte accumulation in the mouse. In cultured cells, p19 ^Arf decreased Pdgfrβ and blocked Pdgf-B-driven proliferation independently of Mdm2 and p53. The presence of a normal Arf allele correlated with decreased Pdgfrβ in the embryonic vitreous. Pdgfrβ was required for vitreous cell accumulation in the absence of Arf. Our findings demonstrate a novel, p53- and Mdm2-independent function for p19^Arf. Instead of solely sensing excessive mitogenic stimuli, developmental cues induce Arf to block Pdgfrβ-dependent signals and prevent the accumulation of perivascular cells selectively in a vascular bed destined to regress.