Notch Signaling between Cerebellar Granule Cell Progenitors
Notch Signaling between Cerebellar Granule Cell Progenitors
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DOI：
10.1523/eneuro.0468-20.2021
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发表时间：
2021-05-01
期刊：
影响因子：
3.4
通讯作者：
Hoshino, Mikio
中科院分区：
文献类型：
--
作者：
Adachi, Toma;Miyashita, Satoshi;Hoshino, Mikio
小脑颗粒细胞（Cerebellar granule cells，GC）是一种细胞，在整个神经系统中占50%以上的神经元。GC使小脑能够适当地调节运动协调，学习和巩固，以及认知，情感和语言。在GC发育过程中，母体颗粒细胞祖细胞（GCPs）不仅分裂产生有丝分裂后的GC，而且产生姐妹GCPs。然而，调节不同的姐妹细胞类型从看似统一的GCP的比例生产的分子机制尚未完全理解。在这里，我们报告说，Notch信号产生了GCPs之间的区别，并导致它们在小鼠中的比例分化。在Notch相关分子中，Notch 1，2，Jag 1和Hes 1在GCP中显著表达。Hes 1启动子活性的体内监测表明，在外部颗粒层（EGL）中存在两种类型的GCPs，Notch信号ON和OFF。单细胞RNA测序和计算机分析表明，ON-GCPs具有更多的增殖和不成熟特性，而OFF-GCPs具有相反的特性。使用体内电穿孔的过表达以及敲低实验表明，NOTCH 2和HES 1参与细胞自主地通过抑制NEUROD 1表达来抑制GCP分化。相反，表达JAG 1的细胞通过周围GCPs中的NOTCH 2-HES 1非自主上调Notch信号传导活性，最终抑制其分化。这些发现表明，Notch信号导致两种类型的细胞（未成熟和分化中的GCPs）成比例地产生，这有助于GCs的良好组织分化。
Cerebellar granule cells (GCs) are cells which comprise over 50 percent of the neurons in the entire nervous system. GCs enable the cerebellum to properly regulate motor coordination, learning, and consolidation, in addition to cognition, emotion and language. During GC development, maternal granule cell progenitors (GCPs) divide to produce not only postmitotic GCs but also sister GCPs. However, the molecular machinery for regulating the proportional production of distinct sister cell types from seemingly uniform GCPs is not yet fully understood. Here we report that Notch signaling creates a distinction between GCPs and leads to their proportional differentiation in mice. Among Notch-related molecules, Notch1, 2, Jag1 and Hes1 are prominently expressed in GCPs. In vivo monitoring of Hes1-promoter activities showed the presence of two types of GCPs, Notch-signaling ON and OFF, in the external granule layer (EGL). Single cell RNA sequencing and in silico analyses indicate that ON-GCPs have more proliferative and immature properties, while OFF-GCPs have opposite characteristics. Overexpression as well as knockdown experiments using in vivo electroporation showed that NOTCH2 and HES1 are involved cell-autonomously to suppress GCP differentiation by inhibiting NEUROD1 expression. In contrast, JAG1-expressing cells non-autonomously upregulated Notch signaling activities via NOTCH2-HES1 in surrounding GCPs, eventually suppressing their differentiation. These findings suggest that Notch signaling results in the proportional generation of two types of cells, immature and differentiating GCPs, which contributes to the well-organized differentiation of GCs.