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.干细胞在复杂且动态的微环境中发生细胞分化，该微环境内的指导性信号会在不同时间尺度上发生波动。因此，细胞必须具备对信号时序做出精准响应的能力，例如区分持续性信号与瞬时噪声。然而，目前对于干细胞如何响应分化信号的动态变化，相关研究尚不够充分。本研究通过光遗传激活β-连环蛋白（β-catenin）信号通路，探究正在分化的成年神经干细胞（NSCs）的动态响应特征。我们发现，持续性升高的β-连环蛋白激活会依次促进细胞增殖与分化，而瞬时性的β-连环蛋白激活则会诱导细胞凋亡。通过基因扰动实验，我们揭示该神经发生/细胞凋亡命运转换是通过生长停滞与DNA损伤诱导蛋白45γ（Gadd45g）介导的细胞周期调控过程实现的。综上，本研究揭示了β-连环蛋白的动态变化在神经干细胞命运决定中的作用，并提示信号时序可通过类似干细胞分化的动力学校正机制，最小化细胞命运决策误差，为该领域提供了全新的研究视角。