Does the Time of Inactivation of pRb Determine the Cell of Origin of Retinoblastoma?

We read with interest a recent paper by Pajovic et al., ¹ on the TAg-RB murine retinoblastoma cell of origin. We would like the authors to answer a few queries that may help us to understand the work better. The expression of TAg was first observed in the nuclei of sparse cells within the inner nuclear layer at P8, the period during which Müller and bipolar cells are generated. When we look at the retinal cell lineage, the other retinal cells including the cone photoreceptors would have undergone differentiation by that period. ² As retinal cells strictly follow the competence model for retinal development, ³ Müller cells and bipolar cells are generated between postnatal day P4 and P6. ² So, it is not surprising that the cells stain for maturing progenitors like Müller and bipolar cells. 

Xu et al. ⁴ reported human retinoblastoma to have properties of a cone precursor. If P8 is the period during which pRB and p53 are inactivated by the transgene in TAg-RB murine retinoblastoma model, the equivalent period in the human fetus would be 19 weeks, ² the stage at which ganglion cells and cone photoreceptors would have already evolved. Could it be that, in human retinoblastoma, the timing of pRB inactivation is much earlier—that is, during the stage at which the cones evolve? Using cone precursor markers such as CRX, RXRγ, and TRβ₂ to stain the mouse tumor might be useful in identifying the cone cell status in this model. Further, as the authors rightly pointed out, the genetic changes after RB1 loss have to be evaluated in the other murine retinoblastoma models before concluding that the TAg-RB murine retinoblastoma model is a good one for the study of therapies for human retinoblastoma.