Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 15, Pages 6285-6290Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0902310106
Keywords
conditional Arf-null mouse; PDGF signaling; spermatogenesis; vitreal hyaloid vasculature
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Funding
- National Cancer Institute Cancer Center Core [CA-21765]
- American Lebanese Syrian Associated Charities
- St. Jude Children's Research Hospital
- Howard Hughes Medical Institute
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The Arf tumor suppressor is expressed transiently during mouse male germ cell and eye development. Its inactivation compromises spermatogenesis as mice age and leads to aberrant postnatal proliferation of cells in the vitreous of the eye, resulting in blindness. In the testis, expression of p19(Arf) is limited to spermatogonia but is extinguished completely in spermatocytes, suggesting that Arf plays a physiologic role in setting the balance between mitotic and meiotic germ cell division. A knock-in allele encoding Cre recombinase regulated by the mouse cellular Arf promoter was used to trace Arf gene induction in vivo. Interbreeding to a reporter strain that expresses Cre-dependent YFP provided proof-of-principle that the Arf-Cre allele was appropriately expressed in the male germ cell lineage. However, Cre expression resulted in male sterility, limiting germ line transmission of the knock-in allele to females. Arf-null mice fail to resorb the hyaloid vasculature within the ocular vitreous where pericyte-like cells that express the PDGF-beta receptor (Pdgfr beta) proliferate aberrantly and destroy the retina and lens. Interbreeding of Arf-Cre females to males containing floxed'' (FL) Arf alleles yielded Arf(Cre/FL) progeny that exhibited variably penetrant defects in visual acuity ranging to total blindness. Crossing the Arf(Cre/FL) alleles onto a Pdgfr(beta FL/FL) background normalized all histopathology and restored vision fully.
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