The RB Protein Family in Retinal Development and Retinoblastoma: New Insights from New Mouse Models

Abstract

The Rb gene was isolated almost 20 years ago, but fundamental questions regarding its role in retinal development and retinoblastoma remain. What is the normal function of RB protein in retinogenesis? What is the cell-of-origin of retinoblastoma? Why do retinoblastoma tumors have recurrent genetic lesions other than Rb inactivation? Why is retinoblastoma not induced by defects in cell cycle regulators other than Rb? Why is the retina so sensitive to Rb loss? Recently developed conditional Rb knockout models provide new insight into some of these issues. The data suggest that RB protein may not control the rate of progenitor division, but is critical for cell cycle exit when dividing retinal progenitors differentiate into postmitotic transition cells. This finding focuses attention on the ectopically dividing transition cell, rather than the progenitor, as the cell-of-origin. Cell-specific analyses in the RB-deficient retina reveal that ectopically dividing photoreceptors, bipolar and ganglion cells die, but amacrine, horizontal and Müller cells survive and stop dividing when they terminally differentiate. Rare amacrine transition cells escape cell cycle exit and generate tumors. These data suggest that post-Rb mutations are required to overcome growth arrest associated with terminal differentiation, rather than apoptosis as previously suggested. To explain why perturbing cell cycle regulators other than RB does not initiate retinoblastoma, we speculate that mutations in other components of the RB pathway perturb cell cycle arrest, but only RB loss triggers genome instability in retinal transition cells, which may be critical to facilitate post-Rb mutations necessary for transformation. Cell-specific differences in the effect of Rb loss on genome stability may contribute to the tremendous sensitivity of retinal transition cells to tumorigenesis. The new mouse models of retinoblastoma will be invaluable for testing these possibilities.

When cell cycle meets development

“…RB gene mutations lead to retinoblastoma in humans, but the mouse retina exhibits extra protection against retinoblastoma such that an additional Rb family member [p107 (Rbl1) or p130 (Rbl2)] needs to be deleted to induce tumourigenesis (Berman et al, 2009;Bremner et al, 2004;Chen et al, 2004). Rod Bremner (Toronto Western Research Institute, Canada) suggested that understanding p107/p130 function in the retina might provide strategies to block other Rb pathway tumours.…”

Retinoblastoma - Genetic Counseling and Molecular Diagnosis

“…The pRB protein is involved not only in regulation of the cell cycle, but also in control of termination of cellular differentiation and in exit of the cell from the cell cycle during development. It appears to interact with more than 100 different proteins (Zhu, 2005, Classon&Harlow, 2002, Chau&Wang, 2003, Bremner et al, 2004. It is probably this role in differentiation which explains the spatiotemporal specificity of the tumour risk associated with RB1 gene mutations and consequently damage to retinal neuroectodermal cells during early childhood.…”

E2F4 Is Required for Early Eye Patterning

“…Since previous studies revealed the important roles of Rb and E2F protein families in eye development [1,3,13] , we asked if one of its regulatory targets, E2F4, also played a unique role in this process. E2F4 is ubiquitously expressed, including the neuroepithelium of the developing optic cup and stalk ( fig.…”