Arf and Eye Development

Stained tissue slice
H&E stained sections showing lack of vascular regression in Arf -/- embryos

It has long been recognized that mice lacking functional p53 or functional Arf (which encodes the p19Arf tumor suppressor protein) develop a wide range of cancers with age. The dogma held that Arf expression is induced by oncogenic signals (like Myc or activated Ras) to activate p53 in a simple linear pathway; neither Arf nor p53 was felt to play a substantial role in development.

Members of the Skapek laboratory, though, discovered that mice lacking Arf are also blind, whereas mice lacking p53 usually have normal vision. Without Arf, early stages of ocular development proceed normally, but at later states, an ocular vascular system that is supposed to regress fails to do so. This dysfunction results in catastrophic damage to the retina and the lens and mimics a congenital human eye disease known as Persistent Hyperplastic Primary Vitreous (PHPV). PHPV was described close to 100 years ago but still lacks a clear genetic cause.

Over the past eight years, the Skapek laboratory team has made and characterized genetically engineered mouse models to identify a new biochemical and genetic pathway governing the actions of Arf to foster vascular regression in the developing eye.

Mouse littermates with differing eye sizes
The eyes of Arf-/- mice (right) are smaller than those of their wild-type littermates.

We now know that in pericytes flanking certain vessels in the eye, Arf expression requires Transforming Growth Factor-beta-2. P19Arf expression in these pericytes limits the expression of Platelet-derived growth factor receptor-beta to control the number of these pericytes. (And p19Arf appears to do so in a manner that does not depend on p53.) Without Tgfb2 or Arf, deregulated Pdgfrb drives excess proliferation of pericytes to support the underlying vasculature, leading to its persistence and the consequent ocular damage.

Ongoing work is focused on understanding more details regarding how Tgfb2 influences Arf expression and how p19Arf controls Pdgfrb. Given that Tgfb2 and Pdgfrb are also known to influence cancer biology, we are especially interested in determining how deregulation of this pathway influences cancer biology. We are focusing on both cancer cell-intrinsic effects like excess Pdgfrb-driven proliferation, and also cell-extrinsic effects such as enhancing tumor-induced angiogenesis.