美国杜克大学Debra L. Silver研究团队近日取得一项新成果。经过不懈努力，他们研制了一种人类特异性的增强剂对放射状胶质细胞的效力和皮质生成进行微调。该研究于2025年5月14日发表于国际一流学术期刊《自然》杂志上。

通过基因组编辑小鼠（Mthem mthemculthem, Mm）和灵长类动物模型，研究组证明了人类（Homo sapiens, Hs） HARE5通过控制神经祖细胞的增殖和神经发生能力来微调皮质发育和连通性。Hs-HARE5敲入小鼠的新皮质显著增大，包含更多兴奋性神经元。通过测量体内的神经动力学，该团队发现这些解剖特征导致皮质区域之间的功能独立性增加。该课题组研究人员评估了潜在的发育机制，主题为固定和实时成像，谱系分析和单细胞RNA测序。

研究人员发现Hs-HARE5改变放射状胶质细胞的行为，在早期发育阶段增加自我更新，随后扩大神经发生潜力。使用基因组编辑的人类和黑猩猩神经祖细胞和皮质类器官，研究小组发现它们的人类特异性Hs-HARE5变体驱动增强子活性增加，促进祖细胞增殖。最后，该课题组研究人员发现Hs-HARE5通过扩增典型的WNT信号来增加祖细胞的增殖。这些发现阐明了调节DNA的微小变化如何直接影响调节大脑发育的关键信号通路。他们的研究揭示了HARs的新功能，它是人类大脑皮层扩张和复杂的关键调控元件。

据悉，人类已经进化出了一个与发育和基因调控修饰相关的异常扩展和复杂的大脑皮层。人类加速区（HARs）是高度保守的DNA序列，具有人类特异性的核苷酸替换。尽管有许多注释的HARs，但它们对物种特异性皮质发育的功能贡献在很大程度上仍然未知。HARE5是WNT信号受体Frizzled8的HAR转录增强子，在大脑发育过程中活跃。

附：英文原文

Title: A human-specific enhancer fine-tunes radial glia potency and corticogenesis

Author: Liu, Jing, Mosti, Federica, Zhao, Hanzhi T., Lollis, Davoneshia, Sotelo-Fonseca, Jesus E., Escobar-Tomlienovich, Carla F., Musso, Camila M., Mao, Yiwei, Massri, Abdull J., Doll, Hannah M., Moss, Nicole D., Sousa, Andre M. M., Wray, Gregory A., Schmidt, Ewoud R. E., Silver, Debra L.

Issue&Volume: 2025-05-14

Abstract: Humans have evolved an extraordinarily expanded and complex cerebral cortex associated with developmental and gene regulatory modifications1,2,3. Human accelerated regions (HARs) are highly conserved DNA sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to species-specific cortical development remains largely unknown4,5. HARE5 is a HAR transcriptional enhancer of the WNT signalling receptor Frizzled8 that is active during brain development6. Here, using genome-edited mouse (Mus musculus, Mm) and primate models, we demonstrated that human (Homo sapiens, Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacities of neural progenitor cells. Hs-HARE5 knock-in mice have significantly enlarged neocortices, containing more excitatory neurons. By measuring neural dynamics in vivo, we showed that these anatomical features result in increased functional independence between cortical regions. We assessed underlying developmental mechanisms using fixed and live imaging, lineage analysis and single-cell RNA sequencing. We discovered that Hs-HARE5 modifies radial glial cell behaviour, with increased self-renewal at early developmental stages, followed by expanded neurogenic potential. Using genome-edited human and chimpanzee (Pan troglodytes, Pt) neural progenitor cells and cortical organoids, we showed that four human-specific variants of Hs-HARE5 drive increased enhancer activity that promotes progenitor proliferation. Finally, we showed that Hs-HARE5 increased progenitor proliferation by amplifying canonical WNT signalling. These findings illustrate how small changes in regulatory DNA can directly affect critical signalling pathways to modulate brain development. Our study uncovered new functions of HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

DOI: 10.1038/s41586-025-09002-1

Source: https://www.nature.com/articles/s41586-025-09002-1