Arx Expression Suppresses Ventralization of the Developing Dorsal Forebrain
Arx Expression Suppresses Ventralization of the Developing Dorsal Forebrain
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DOI：
10.1038/s41598-018-36194-6
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发表时间：
2019-01-18
影响因子：
4.6
通讯作者：
Golden, Jeffrey A.
中科院分区：
文献类型：
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作者：
Lim, Youngshin;Cho, Il-Taeg;Golden, Jeffrey A.
早期大脑发育需要神经管模式和生长之间的紧密协调。模式形成和大脑生长如何协调尚不完全清楚。之前我们表明，aristaless 相关同源盒（ARX）是一种配对样转录因子，通过抑制细胞周期进程的抑制剂来调节皮质祖细胞库的扩张。在这里，我们表明 ARX 参与建立小鼠前脑的背腹侧身份。在 Arx 突变小鼠中，包括 Olig2 在内的腹侧基因在背部异位表达。此外，Gli1 上调，表明 SHH 信号传导异位激活。我们发现，可以通过阻断 SHH 信号传导来抑制异位 Olig2 表达，这表明 SHH 信号传导在 Olig2 诱导中发挥作用。我们进一步证明异位 Olig2 导致 Pax6 和 Tbr2 表达减少，这两个背侧特异性基因对于皮质祖细胞增殖至关重要。这些数据表明祖细胞背腹特性的控制与其增殖的控制之间存在联系。总之，我们的数据表明，ARX 在整合正常前脑模式和生长的基因调控网络中发挥作用，为了解 ARX 突变如何扰乱大脑发育的多个方面，从而产生在人类患者中观察到的广泛的神经发育表型提供了重要的见解。
Early brain development requires a tight orchestration between neural tube patterning and growth. How pattern formation and brain growth are coordinated is incompletely understood. Previously we showed that aristaless-related homeobox (ARX), a paired-like transcription factor, regulates cortical progenitor pool expansion by repressing an inhibitor of cell cycle progression. Here we show that ARX participates in establishing dorsoventral identity in the mouse forebrain. In Arx mutant mice, ventral genes, including Olig2, are ectopically expressed dorsally. Furthermore, Gli1 is upregulated, suggesting an ectopic activation of SHH signaling. We show that the ectopic Olig2 expression can be repressed by blocking SHH signaling, implicating a role for SHH signaling in Olig2 induction. We further demonstrate that the ectopic Olig2 accounts for the reduced Pax6 and Tbr2 expression, both dorsal specific genes essential for cortical progenitor cell proliferation. These data suggest a link between the control of dorsoventral identity of progenitor cells and the control of their proliferation. In summary, our data demonstrate that ARX functions in a gene regulatory network integrating normal forebrain patterning and growth, providing important insight into how mutations in ARX can disrupt multiple aspects of brain development and thus generate a wide spectrum of neurodevelopmental phenotypes observed in human patients.