b-catenin Signaling Dynamics Regulate Cell Fate in Differentiating Neural Stem Cells

Stem cells undergo differentiation in complex and dynamic environments wherein instructive signals fluctuate on various timescales. Thus, cells must be equipped to properly respond to the timing of signals, for example to distinguish sustained signaling from transient noise. However, how stem cells respond to dynamic variations in differentiation cues is not well characterized. Here, we use optogenetic activation of b-catenin signaling to probe the dynamic responses of differentiating adult neural stem cells (NSCs). We discover that while elevated, sustained b-catenin activation sequentially promotes proliferation and differentiation, transient b-catenin induces apoptosis. Genetic perturbations revealed that the neurogenic/apoptotic fate-switch was mediated through cell cycle regulation by Growth Arrest and DNA Damage 45 gamma (Gadd45g). Our results thus reveal a role for b-catenin dynamics in NSC fate decisions and may suggest a novel role for signal timing to minimize cell fate errors, analogous to kinetic proofreading of stem cell differentiation. Overall design: RNA profiles of adult rat neural stem cells subjected to Wnt/b-catenin stimulation over 3-5 days. Stimulation was achieved using either CHIR99021 (3 mM), Wnt 3a (100 ng/mL), or optogenetics (optoWnt). Stimulation was applied for one day and was subsequently withdrawn for days 2 and 3. Control conditions include cells that received no stimulation, or cells that received constant stimulation over 3-5 days.