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Persistent hyperplastic primary vitreous due to somatic mosaic deletion of the arf tumor suppressor
J Derek Thornton1, Doug J Swanson, Michelle N Mary
1Department of Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN 38105, USA.
Purpose:
Mice lacking the Arf tumor-suppressor gene develop eye disease reminiscent of persistent hyperplastic primary vitreous (PHPV). The current work explores mechanisms by which Arf promotes eye development, and its absence causes a PHPV-like disease.
Methods:
Chimeric mice were made by fusing wild-type and Arf(-/-) morulae. In these experiments, wild-type cells are identified by transgenic expression of GFP from a constitutive promoter. PCR-based genotyping and quantitative analyses after immunofluorescence staining of tissue and cultured cells documented the relative contribution of wild-type and Arf(-/-) cells to different tissues in the eye and different types of cells in the vitreous.
Results:
The contributions of the Arf(-/-) lineage to the tail DNA, cornea, retina, and retina pigment epithelium (RPE) correlated with each other in wild-type<-->Arf(-/-) chimeric mice. Newborn chimeras had primary vitreous hyperplasia, evident as a retrolental mass. The mass was usually present when the proportion of Arf(-/-) cells was relatively high and absent when the Arf(-/-) proportion was low. The Pdgfrbeta- and Sma-expressing cells within the mass arose predominantly from the Arf(-/-) population. Ectopic Arf expression induced smooth muscle proteins in cultured pericyte-like cells, and Arf and Sma expression overlapped in hyaloid vessels.
Conclusions:
In the mouse model, loss of Arf in only a subset of cells causes a PHPV-like disease. The data indicate that both cell autonomous and non-cell autonomous effects of Arf may contribute to its role in vitreous development.
Insights
Loss of the Arf tumor suppressor gene in mice causes a persistent hyperplastic primary vitreous (PHPV)-like eye disease. This study reveals Arf
Area of Science:
- Developmental biology
- Ophthalmology
- Genetics
Background:
- The Arf tumor suppressor gene plays a critical role in cellular processes.
- Arf deficiency in mice leads to an eye condition resembling persistent hyperplastic primary vitreous (PHPV).
- Understanding Arf's function is crucial for eye development and disease pathogenesis.
Purpose of the Study:
- To investigate the mechanisms by which Arf influences eye development.
- To elucidate how the absence of Arf results in a PHPV-like disease.
- To explore the cellular and genetic basis of Arf's role in the vitreous.
Main Methods:
- Generation of chimeric mice by fusing wild-type and Arf-deficient (Arf(-/-)) morulae.
- Identification of wild-type cells using GFP expression.
- Quantitative analysis of cell contributions to ocular tissues and vitreous using PCR and immunofluorescence.
Main Results:
- Arf(-/-) cell contribution correlated across tail DNA, cornea, retina, and RPE in chimeric mice.
- Primary vitreous hyperplasia (retrolental mass) was observed in newborn chimeras, particularly with high Arf(-/-) cell proportions.
- Pdgfrbeta- and Sma-expressing cells in the mass originated mainly from the Arf(-/-) lineage; Arf induced smooth muscle proteins in pericyte-like cells.
Conclusions:
- Loss of Arf in a subset of cells can induce a PHPV-like disease in a mouse model.
- Both cell-autonomous and non-cell-autonomous functions of Arf are implicated in vitreous development.
- Arf's role extends beyond tumor suppression to critical developmental processes in the eye.
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