美国北卡罗来纳大学医学院E. S. Anton课题组提出了TSC调节新皮层祖细胞平衡和上层神经元生成。这一研究成果于2025年12月3日发表在国际顶尖学术期刊《自然》上。

在这里，研究组发现结节瘤硬化复合体（TSC）的成员-细胞代谢的主要调节蛋白-功能塑造径向祖细胞-中间祖细胞平衡，径向单位组织和由此产生的上层神经元。TSC蛋白的发育缺失改变了径向祖细胞和IP平衡，改变了径向单元组成，导致上层神经元生成增加和皮层连通性异常。通过人获得的增强子对TSC蛋白表达的人类特异性调节影响祖细胞平衡和上层神经元的产生。因此，TSC蛋白表达的进化下调可能为径向单元雕刻和人类高阶脑功能所需的上层神经元的扩大产生提供了有效途径。

据了解，上层神经元的适当生成对于形成构成复杂大脑功能基础的回路是必要的。放射状祖细胞不对称分裂生成神经源性中间祖细胞（intermediate progenitor, IPs，又称中间前体），IPs的对称增殖迅速扩大皮层神经元群体。皮层祖细胞多样性平衡的动态维持，以及相应数量的不同类型神经元的产生、放置和连接，有助于指导大脑皮层的形成。然而，指导祖细胞平衡的分子逻辑仍不清楚。

附：英文原文

Title: TSC tunes progenitor balance and upper-layer neuron generation in neocortex

Author: Casingal, Cristine R., Nakagawa, Naoki, Yabuno-Nakagawa, Keiko, Meyer, Cailyn, Liu, Siling, Gkini, Vasiliki, Cho, Su-Ji, Skarica, Mario, Liang, Dan, Simon, Jeremy M., Matoba, Nana, Mallick, Ahana, Singla, Rubal, Park, Jieun, Huang, Chu-Wei, Wilson, Hailey, Lee, Janice, Ghashghaei, H. Troy, Stuber, Garret D., Heikinheimo, Oskari, Namba, Takashi, Stein, Jason L., Anton, E. S.

Issue&Volume: 2025-12-03

Abstract: The appropriate generation of upper-layer neurons is necessary to create the circuits that underlie complex brain functions. Radial progenitors divide asymmetrically to generate neurogenic intermediate progenitors (IPs; also known as intermediate precursors), and the symmetric proliferation of IPs rapidly expands the cortical neuronal population. The dynamic maintenance of balanced diversity of cortical progenitors and the resultant generation, placement and connectivity of appropriate numbers of different classes of neurons serve to guide the formation of a properly wired cerebral cortex1,2,3,4,5,6,7,8,9,10,11,12. However, the molecular logic that instructs progenitor balance remains unclear. Here we show that members of the tuberous sclerosis complex (TSC)—proteins that are major regulators of cellular metabolism—function to sculpt radial progenitor–intermediate progenitor balance, radial unit organization and the resultant generation of upper-layer neurons. Developmental deletion of TSC proteins alters the radial progenitor and IP balance and changes radial unit composition, leading to increased upper-layer neuron generation and aberrant cortical connectivity. Human-specific modulation of TSC protein expression through human-gained enhancers affects progenitor balance and generation of upper-layer neurons. Evolutionary downregulation of TSC protein expression may therefore provide an effective route to radial unit sculpting and the expanded generation of upper-layer neurons necessary for higher-order brain functions in humans.

DOI: 10.1038/s41586-025-09810-5

Source: https://www.nature.com/articles/s41586-025-09810-5