The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primate Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
Chinese Institute for Brain Research, Beijing 102206, China.
Cereb Cortex. 2021 Jul 29;31(9):4078-4091. doi: 10.1093/cercor/bhab070.
Wnt/β-catenin signaling plays multiple important roles during mammalian brain development, and it regulates the proliferation and differentiation of neural progenitors in a context-dependent manner and affects neocortex layer formation. However, the specific role of Wnt/β-catenin in neuronal layer fate determination in the neocortex is still unclear. Here, we report that Zbed3, which is a positive regulator of Wnt/β-catenin signaling, colocalizes with β-catenin at the endfeet of radial glia in the ventricular zone of embryo mouse neocortex. Overexpression and knockdown of Zbed3 increased and decreased the activity of Wnt/β-catenin signaling in the neocortex, respectively. Interestingly, knockdown of Zbed3 in vivo could significantly shift neuronal fates from deep layers to upper layers but is not required for the proliferation and differentiation of neural progenitors. Overexpression of Zbed3 led to increased generation of deep-layer neurons without impairing cell cycle exit of neural progenitors. More importantly, knockdown of Zbed3 could effectively block the effects of the ectopic expression of stabilized β-catenin on neocortex layer formation. Hence, our results demonstrate that Zbed3 is indispensable for Wnt/β-catenin signaling regulating neuronal layer fates in the developing brain.
Wnt/β-catenin 信号通路在哺乳动物大脑发育过程中发挥着多种重要作用，它以依赖于上下文的方式调节神经祖细胞的增殖和分化，并影响新皮层的层形成。然而，Wnt/β-catenin 在新皮层神经元层命运决定中的具体作用仍不清楚。在这里，我们报告说，Zbed3 是 Wnt/β-catenin 信号通路的正调节剂，与胚胎小鼠新皮层脑室区放射状胶质的足状突中的 β-catenin 共定位。Zbed3 的过表达和敲低分别增加和减少了新皮层中 Wnt/β-catenin 信号的活性。有趣的是，体内敲低 Zbed3 可显著将神经元命运从深层转移到浅层，但对神经祖细胞的增殖和分化不是必需的。Zbed3 的过表达导致深层神经元的产生增加，而不会损害神经祖细胞的细胞周期退出。更重要的是，敲低 Zbed3 可有效阻止稳定化 β-catenin 的异位表达对新皮层层形成的影响。因此，我们的结果表明，Zbed3 对于 Wnt/β-catenin 信号通路调节发育中大脑的神经元层命运是必不可少的。
