Ocular abnormalities in mice lacking the Ski proto-oncogene

Persistent hyperplastic primary vitreous (PHPV) is a developmental ocular malformation often associated with additional ocular abnormalities. This study involved a novel mouse model of PHPV, generated by a null mutation of the Ski proto-oncogene, that displays other anterior segment and retinal malformations often found in human cases of PHPV.

Morphologic and histologic analyses of Ski-/- mice were used to document ocular abnormalities in comparison to those of normal littermates. Immunohistochemical studies were used to examine the expression of relevant markers of ocular and vascular development including Pax6, beta-III tubulin, and Flk1.

PHPV and microphthalmia were found in 100% of Ski-/- fetuses. Other abnormalities included anterior segment and lens dysgenesis, retinal folds, chorioretinal coloboma, and Peters anomaly. The severity was variable, even in a highly homogeneous genetic background. PHPV was characterized by the presence of retrolental fibrous and vascular tissue that did not express the neuronal marker beta-III tubulin, but was positive for Flk1 expression and contained no obviously pigmented cells.

The results show that normal ocular development requires the function of the Ski proto-oncogene, and mice lacking Ski have many features associated with PHPV, and some similarities with Peters anomaly in humans. Defects in Ski-/- mice closely resemble those described in animals lacking several of the retinoic acid receptor genes, or in animals exposed to excess retinoic acid during gestation. Ski has been shown to repress transcription induced by retinoic acid signaling, and may thus affect ocular development by regulating RA signaling.