Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Development. 2020 May 15;147(10):dev185132. doi: 10.1242/dev.185132.
Cortex development is controlled by temporal patterning of neural progenitor (NP) competence with sequential generation of deep and superficial layer neurons, but underlying mechanisms remain elusive. Here, we report a role for heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) in regulating the division of early cortical NPs that mainly give rise to deep-layer neurons via direct neurogenesis. HNRNPA3 is expressed at high levels in NPs of mouse and human cortex at early stages, with a unique peri-chromosome pattern. Intriguingly, downregulation of HNRNPA3 caused chromosome disarrangement, which hindered normal separation of chromosomes during NP division, leading to mitotic delay. Furthermore, HNRNPA3 is associated with the cohesin-core subunit SMC1A and controls its association with chromosomes, implicating a mechanism for the role of HNRNPA3 in regulating chromosome segregation in dividing NPs. -deficient mice exhibited reduced cortical thickness, especially of deep layers. Moreover, downregulation of HNRNPA3 in cultured human cerebral organoids led to marked reduction in NPs and deep-layer neurons. Thus, this study has identified a crucial role for HNRNPA3 in NP division and highlighted the relationship between mitosis progression and early neurogenesis.
皮质发育受神经祖细胞（NP）能力的时间模式控制，随后产生深层和浅层神经元，但潜在机制仍不清楚。在这里，我们报告了异质核核糖核蛋白 A3（HNRNPA3）在调节早期皮质 NP 分裂中的作用，这些 NP 主要通过直接神经发生产生深层神经元。HNRNPA3 在早期的小鼠和人类皮质 NP 中高水平表达，具有独特的染色体周围模式。有趣的是，HNRNPA3 的下调导致染色体排列紊乱，这阻碍了 NP 分裂过程中染色体的正常分离，导致有丝分裂延迟。此外，HNRNPA3 与着丝粒核心亚基 SMC1A 相关，并控制其与染色体的结合，暗示了 HNRNPA3 在调节分裂 NP 中染色体分离的作用机制。HNRNPA3 缺陷小鼠表现出皮质厚度减少，特别是深层。此外，在培养的人类大脑类器官中下调 HNRNPA3 导致 NP 和深层神经元的明显减少。因此，本研究确定了 HNRNPA3 在 NP 分裂中的关键作用，并强调了有丝分裂进展与早期神经发生之间的关系。
