Heterogeneous nuclear ribonucleoprotein A3 controls mitotic progression of neural progenitors via interaction with cohesin
Heterogeneous nuclear ribonucleoprotein A3 controls mitotic progression of neural progenitors via interaction with cohesin
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异质核核糖核蛋白 A3 通过与粘连蛋白相互作用控制神经祖细胞的有丝分裂进程
DOI：
10.1242/dev.185132
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发表时间：
2020-05-01
期刊：
影响因子：
4.6
通讯作者：
Luo, Zhen-Ge
中科院分区：
文献类型：
--
作者：
Ou, Min-Yi;Ju, Xiang-Chun;Luo, Zhen-Ge
大脑皮层的发育是由神经祖细胞（NP）能力的时间模式控制的，深层和浅层神经元的顺序产生，但潜在的机制仍然是难以捉摸的。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NPs的分裂，主要是通过直接神经发生引起深层神经元的作用。HNRNPA3在小鼠和人皮质的NP中早期以高水平表达，具有独特的染色体周围模式。有趣的是，HNRNPA3的下调导致染色体重排，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与粘附素核心亚基SMC1A相关，并控制其与染色体的关联，暗示了HNRNPA3在调节分裂NP的染色体分离中的作用的机制。Hnrnpa3缺陷小鼠表现出皮质厚度减少，尤其是深层。此外，HNRNPA3在培养的人脑类器官中的下调导致NP和深层神经元的显着减少。因此，这项研究已经确定了HNRNPA3在NP分裂中的关键作用，并强调了有丝分裂进程和早期神经发生之间的关系。总结：异质核核糖核蛋白A3是维持有丝分裂神经祖细胞染色体结构的保守分子，是早期出生的皮层神经元正常神经发生所必需的。
ABSTRACT 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. Hnrnpa3-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. Summary: Heterogeneous nuclear ribonucleoprotein A3, a conserved molecule that maintains the chromosome organization in mitotic neural progenitors, is required for proper neurogenesis of early born cortical neurons.