Wnt signaling plays a critical role in production and differentiation of neurons and undergoes a progressive reduction during cortical development. However, how Wnt signaling is regulated is not well understood. Here we provide evidence for an indispensable role of neddylation, a ubiquitylation-like protein modification, in inhibiting Wnt/β-catenin signaling. We show that β-catenin is neddylated; and inhibiting β-catenin neddylation increases its nuclear accumulation and Wnt/β-catenin signaling. To test this hypothesis in vivo, we mutated Nae1, an obligative subunit of the E1 for neddylation in cortical progenitors. The mutation leads to eventual reduction in radial glia progenitors (RGPs). Consequently, the production of intermediate progenitors (IPs) and neurons is reduced, and neuron migration is impaired, resulting in disorganization of the cerebral cortex. These phenotypes are similar to those of β-catenin gain-of-function mice. Finally, suppressing β-catenin expression is able to rescue deficits of Nae1 mutant mice. Together, these observations identified a mechanism to regulate Wnt/β-catenin signaling in cortical development.

Wnt 信号传导在神经元的产生和分化中发挥着关键作用，并在皮质发育过程中逐渐减少。然而，Wnt 信号传导是如何调节的尚不清楚。在这里，我们提供了证据，证明 neddylation（一种类似泛素化的蛋白质修饰）在抑制 Wnt/β-catenin 信号传导中发挥着不可或缺的作用。我们证明 β-catenin 是 neddylated 的；抑制 β-catenin neddylation 会增加其核积累和 Wnt/β-catenin 信号传导。为了在体内验证这一假设，我们对 Nae1 进行了突变，Nae1 是皮质祖细胞中 E1 的 neddylation 必需亚基。该突变导致放射状胶质祖细胞（RGP）最终减少。因此，中间祖细胞（IP）和神经元的产生减少，神经元迁移受损，导致大脑皮层紊乱。这些表型与 β-连环蛋白功能获得小鼠的表型相似。最后，抑制 β-catenin 表达能够挽救 Nae1 突变小鼠的缺陷。总之，这些观察结果确定了一种调节皮质发育中 Wnt/β-连环蛋白信号传导的机制。