Smad4 and Trim33/Tif1γ Redundantly Regulate Neural Stem Cells in the Developing Cortex

During central nervous system (CNS) development, proliferation and differentiation of neural stem cells (NSCs) have to be regulated in a spatio-temporal fashion. Here, we report different branches of the transforming growth factor beta (TGF beta) signaling pathway to be required for the brain area-specific control of NSCs. In the midbrain, canonical TGF beta signaling via Smad4 regulates the balance between proliferation and differentiation of NSCs. Accordingly, Smad4 deletion resulted in horizontal expansion of NSCs due to increased proliferation, decreased differentiation, and decreased cell cycle exit. In the developing cortex, however, ablation of Smad4 alone did not have any effect on proliferation and differentiation of NSCs. In contrast, concomitant mutation of both Smad4 and Trim33 led to an increase in proliferative cells in the ventricular zone due to decreased cell cycle exit, revealing a functional redundancy of Smad4 and Trim33. Furthermore, in Smad4-Trim33 double mutant embryos, cortical NSCs generated an excess of deep layer neurons concurrent with a delayed and reduced production of upper layer neurons and, in addition, failed to undergo the neurogenic to gliogenic switch at the right developmental stage. Thus, our data disclose that in different regions of the developing CNS different aspects of the TGF beta signaling pathway are required to ensure proper development.