Intermediate progenitors and Tbr2 in cortical development
Intermediate progenitors and Tbr2 in cortical development
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DOI：
10.1111/joa.12939
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发表时间：
2019-09-01
影响因子：
2.4
通讯作者：
Hevner, Robert F.
中科院分区：
文献类型：
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作者：
Hevner, Robert F.
在发育中的大脑皮层中，中间祖细胞 (IP) 是特异性表达 Tbr2（基因：Eomes）（一种 T 盒转录因子）的转运放大细胞。 IP 源自放射状胶质细胞 (RG) 祖细胞，即发育中的皮质的神经干细胞。反过来，IP 专门生成谷氨酸能投射神经元 (PN)。 IP 存在于心室和室下区，它们区分为不同的心室 IP (vIP) 和外部 IP (oIP) 亚型。从形态学上讲，IP 具有短的过程，类似于丝状伪足或神经突，可短暂接触其他细胞，最重要的是分裂 RG 细胞以介导 Delta-Notch 信号传导。此外，IP 还分泌一种趋化因子 Cxcl12，它引导中间神经元和小胶质细胞迁移并促进丘脑皮质轴突生长。在小鼠中，IP 产生 1-12 个 PN 的克隆，有时跨越多个层。有丝分裂后，IP 子细胞在大多数情况下都会经历不对称细胞死亡。在小鼠中，Tbr2 对于 PN 分化和亚型规范以及抑制 IP 基因转录因子是必需的。 Tbr2 直接抑制 Insm1（一种 IP 基因转录因子基因）以及 Pax6（Tbr2 转录的关键激活剂）。如果没有 Tbr2，异常 IP 的数量会暂时积累。更广泛地说，Tbr2 通过激活或抑制数百个直接靶基因来调节转录组。值得注意的是，Tbr2 通过招募 Jmjd3（一种组蛋白 H3K27me3 去甲基酶，可去除多梳抑制复合物 2 所放置的抑制性表观遗传标记）来“解锁”并激活 PN 特异性基因，例如 Tbr1。IP 在哺乳动物大脑皮层的进化和回旋中发挥着重要作用，而 TBR2 对于人类大脑发育至关重要。
In developing cerebral cortex, intermediate progenitors (IPs) are transit amplifying cells that specifically express Tbr2 (gene: Eomes), a T-box transcription factor. IPs are derived from radial glia (RG) progenitors, the neural stem cells of developing cortex. In turn, IPs generate glutamatergic projection neurons (PNs) exclusively. IPs are found in ventricular and subventricular zones, where they differentiate as distinct ventricular IP (vIP) and outer IP (oIP) subtypes. Morphologically, IPs have short processes, resembling filopodia or neurites, that transiently contact other cells, most importantly dividing RG cells to mediate Delta-Notch signaling. Also, IPs secrete a chemokine, Cxcl12, which guides interneuron and microglia migrations and promotes thalamocortical axon growth. In mice, IPs produce clones of 1-12 PNs, sometimes spanning multiple layers. After mitosis, IP daughter cells undergo asymmetric cell death in the majority of instances. In mice, Tbr2 is necessary for PN differentiation and subtype specification, and to repress IP-genic transcription factors. Tbr2 directly represses Insm1, an IP-genic transcription factor gene, as well as Pax6, a key activator of Tbr2 transcription. Without Tbr2, abnormal IPs transiently accumulate in elevated numbers. More broadly, Tbr2 regulates the transcriptome by activating or repressing hundreds of direct target genes. Notably, Tbr2 'unlocks' and activates PN-specific genes, such as Tbr1, by recruiting Jmjd3, a histone H3K27me3 demethylase that removes repressive epigenetic marks placed by polycomb repressive complex 2. IPs have played an important role in the evolution and gyrification of mammalian cerebral cortex, and TBR2 is essential for human brain development.