# Rb substantially compensates for the double loss of p130 and p107 in adult but not embryonic neural stem cell lineages

## TL;DR

The Rb protein compensates for the loss of p130 and p107 in adult neural stem cells but not in embryos, affecting neurogenesis and survival.

## Contribution

This study identifies Rb as a critical compensatory factor in adult neurogenesis and reveals dose-dependent roles of pocket proteins during development.

## Key findings

- TKO of pocket proteins causes niche depletion and loss of neurogenesis in the adult olfactory bulb.
- Rb compensates for p107 and p130 loss in adult NSCs but not in embryos.
- Notch-Hes signaling is deregulated oppositely in embryonic and adult brains.

## Abstract

The Retinoblastoma (Rb) family of pocket proteins (p107, Rb, and p130) controls all aspects of neurogenesis from stem cell activation to long-term neuronal survival in the brain. Previous studies have reported non-overlapping, often complementary, roles for these cell cycle regulators with possibility for functional compensation. Yet the extent to which each protein might compensate for other family members and whether synergistic effects exist during neural stem cell (NSC) lineage development remain unclear. Fong et al. recently revealed that a triple knock-out (TKO) of all pocket proteins results in a transcriptomic switch from NSC quiescence to activation, followed by niche depletion in the adult hippocampus. Here, we investigated whether pocket proteins are equally critical in NSC fate regulation in the adult subventricular zone (aSVZ) and during embryogenesis. We report that TKO of these proteins results in NSC activation coupled to ectopic progenitor proliferation and massive apoptosis, leading to niche depletion and premature loss of neurogenesis inside the olfactory bulb (OB). Notably, a p107–p130 double knockout carrying a single wild-type Rb allele (DKO) substantially rescues the above defects and maintains adult neurogenesis. In comparison, TKO embryos display severe disruptions in all stages of neurogenesis at E14.5, leading to embryonic lethality. Similar defects are detected when any five out of the six alleles of pocket proteins are lost, with only partial rescue of the proliferation defects observed in DKO embryos. The above TKO phenotypes are partially mediated by opposed deregulations in the Notch-Hes signaling pathway in the embryonic versus the adult brain. Such deregulation is linked to opposite changes in E2F3a and E2F3b embryonic gene expressions. Our data identifies Rb as a critical pocket protein in the control and maintenance of adult OB neurogenesis, and uncovers interchangeable, dose-dependent roles for pocket proteins in the control of neuronal differentiation and survival during development.