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  • The EMBO Journal (2005) 24, 2803 - 2814
  • doi:10.1038/sj.emboj.7600751

Published online: 21 July 2005

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

Ricardo LA Silva1, J Derek Thornton1, Amy C Martin1, Jerold E Rehg2, David Bertwistle3,4, Frederique Zindy3 and Stephen X Skapek1

  1. Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
  2. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA
  3. Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA
  4. Howard Hughes Medical Institute, St Jude Children's Research Hospital, Memphis, TN, USA

Correspondence to:

Stephen X Skapek, Department of Hematology/Oncology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA. Tel.: +1 901 495 4019; Fax: +1 901 495 3966; E-mail: Steve.Skapek@stjude.org

Received 27 January 2005; Accepted 27 June 2005

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 beta (Pdgfrbeta), which is essential for pericyte accumulation in the mouse. In cultured cells, p19Arf decreased Pdgfrbeta and blocked Pdgf-B-driven proliferation independently of Mdm2 and p53. The presence of a normal Arf allele correlated with decreased Pdgfrbeta in the embryonic vitreous. Pdgfrbeta was required for vitreous cell accumulation in the absence of Arf. Our findings demonstrate a novel, p53- and Mdm2-independent function for p19Arf. Instead of solely sensing excessive mitogenic stimuli, developmental cues induce Arf to block Pdgfrbeta-dependent signals and prevent the accumulation of perivascular cells selectively in a vascular bed destined to regress.

  • Keywords:

    • eye development,
    • p19Arf,
    • pericytes,
    • platelet-derived growth factor,
    • tumor suppressor gene