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 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.
Silva
Ricardo L A
RL
Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
Thornton
J Derek
JD
Martin
Amy C
AC
Rehg
Jerold E
JE
Bertwistle
David
D
Zindy
Frederique
F
Skapek
Stephen X
SX
D000818:Animals; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005123:Eye / Q000166:cytology* / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D020797:Receptor, Platelet-Derived Growth Factor beta