Tgfβ Signaling Regulates Temporal Neurogenesis and Potency of Neural Stem Cells in the CNS

How the sequential specification of neurons and progressive loss of potency associated with aging neural progenitors are regulated in vertebrate brain development is poorly understood. By examining a temporal differentiation lineage in the hindbrain, we here identify Tgf beta as a switch signal that executes the transition between early and late phases of neurogenesis and concurrently constrains progenitor potency. Young progenitors have inherent competence to produce late-born neurons, but implementation of late-differentiation programs requires suppression of early identity genes achieved through temporally programmed activation of Tgf beta downstream of Shh signaling. Unexpectedly, we find that sequentially occurring fate-switch decisions are temporally coupled, and onset of Tgf beta signaling appears thereby to impact on the overall lifespan of the temporal lineage. Our study establishes Tgf beta as a regulator of temporal identity and potency of neural stem cells, and provides proof of concept that Tgf beta can be applied to modulate temporal specification of neurons in stem cell engineering.