Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma.

Retinogenesis involves expansion of pluripotent progenitors, specification of postmitotic precursors, and terminal differentiation. Rb or Rb/p107 loss causes retinoblastoma in humans or mice, respectively. One model suggests that Rb- or Rb/p107-deficient retinal precursors have infinite proliferative capacity but are death-prone and must acquire an antiapoptotic mutation. Indeed, we show that Rb/p107 loss does not affect progenitor proliferation or precursor specification, but perturbs cell cycle exit in all seven retinal precursors. However, three precursors survive Rb/p107-loss and stop proliferating following terminal differentiation. Tumors arise from precursors that escape this delayed growth arrest. Thus, retinoblastoma arises from a precursor that has extended, not infinite, proliferative capacity, and is intrinsically death-resistant, not death-prone. We suggest that additional lesions common in retinoblastoma overcome growth arrest, not apoptosis.

The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis.

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal "birthdating" confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.