Compensation by p107 Following Rb Gene Inactivation Prevents Retinoblastoma in Mice But Not Humans

Abstract

 

Abstract:

 

The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene cloned in humans and one of the first tumor suppressor genes knocked out in mice. Children who inherit one defective copy of the RB1 gene are likely to develop bilateral multifocal retinoblastoma whereas Rb^+/– mice do not develop this debilitating intraocular cancer. We have found that mice are resistant to retinoblastoma formation following Rb gene inactivation because of intrinsic genetic compensation by a related family member (p107) in retinal progenitor cells during development. By conditionally inactivating both Rb and p107 in proliferating retinal progenitor cells in vivo, we generated the first knockout mouse model of retinoblastoma that recapitulates the human disease (shown). More recently we have generated clones of cells lacking Rb and p107 by injecting a Cre–expressing retrovirus into the eyes of newborn Rb^Lox/–;p107^–/– mice. To study the contribution of p53 to retinal tumorigenesis, similar experiments were performed with Rb^Lox/–;p107^–/–;p53^Lox/– mice. In addition to traditional clonal analysis, we have use two–photon live imaging to follow the expansion of clones lacking Rb, p107 and p53. To test whether p107 compensation can occur in human retinal progenitor cells we have knocked down RB1 gene expression by introducing an interfering RNA by square wave electroporation into human fetal retinae. Current efforts are focused on elucidating the mechanism underlying differential p107 compensation in humans and mice and how this contributes to tumorigenesis.

 

 

 

Keywords: retinoblastoma • retinal development • genetics