MicroRNA-9 Regulates Neurogenesis in Mouse Telencephalon by Targeting Multiple Transcription Factors
MicroRNA-9 Regulates Neurogenesis in Mouse Telencephalon by Targeting Multiple Transcription Factors
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DOI：
10.1523/jneurosci.5085-10.2011
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发表时间：
2011-03-02
影响因子：
5.3
通讯作者：
Aizawa, Shinichi
中科院分区：
文献类型：
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作者：
Shibata, Mikihito;Nakao, Hiromi;Aizawa, Shinichi
microRNA-9-2和microRNA-9-3双突变小鼠证明，microRNA-9（miR-9）通过调节多种转录因子的表达来控制发育中端脑中神经祖细胞的增殖和分化。正如我们之前的研究所表明的，Foxg 1表达升高，Cajal-Retzius细胞和早期出生的神经元的产生在miR-9-2/3双突变体paleumen中受到抑制。然而，在胚胎第16.5天（E16.5），Foxg 1的表达不再升高。富含AU的RNA结合蛋白Elav 12的表达在E16.5增加，Elav 2与Foxg 1 3'非翻译区（UTR）相关，并且其对抗miR-9对Foxg 1的抑制。随后，随着Nr 2 e1和Pax 6表达的减少以及Meis 2表达的增加，miR-9-2/3双突变体paleuminescence中的祖细胞增殖减少。分析表明，microRNA-9通过抑制Meis 2表达间接抑制Pax 6表达。相反，microRNA-9与Elavl 1和Msi 1一起靶向Nr 2 e1 mRNA 3' UTR以增强表达。同时，在miR-9-2/3双突变体中，皮质层减少，每个皮质突起畸形，并且中间神经元向腭板的切向迁移受损。miR-9还靶向Gsh 2 3' UTR，并且Gsh 2以及Foxg 1的表达在miR-9-2/3双突变体的腭下突中升高。结果表明，大鼠的基底神经节包括纹状体和苍白球的发育受到抑制，而基底神经节的增殖受到抑制。Pallial/sub-pallial边界背侧移位，腹侧Pallial丢失。在miR-9-2/3双突变体中，走廊畸形，丘脑皮质和离皮质轴突走错路线。
microRNA-9-2 and microRNA-9-3 double-mutant mice demonstrate that microRNA-9 (miR-9) controls neural progenitor proliferation and differentiation in the developing telencephalon by regulating the expression of multiple transcription factors. As suggested by our previous study, the Foxg1 expression was elevated, and the production of Cajal-Retzius cells and early-born neurons was suppressed in the miR-9-2/3 double-mutant pallium. At embryonic day 16.5 (E16.5), however, the Foxg1 expression was no longer elevated. The expression of an AU-rich RNA-binding protein Elavl2 increased at E16.5, Elav2 associated with Foxg1 3' untranslated region (UTR), and it countered the Foxg1 suppression by miR-9. Later, progenitor proliferation was reduced in the miR-9-2/3 double-mutant pallium with the decrease in Nr2e1 and Pax6 expression and the increase in Meis2 expression. The analyses suggest that microRNA-9 indirectly inhibits Pax6 expression by suppressing Meis2 expression. In contrast, together with Elavl1 and Msi1, microRNA-9 targets Nr2e1 mRNA 3' UTR to enhance the expression. Concomitantly, cortical layers were reduced, each cortical projection was malformed, and the tangential migration of interneurons into the pallium was impaired in the miR-9-2/3 double mutants. miR-9 also targets Gsh2 3' UTR, and Gsh2, as well as Foxg1, expression was elevated in the miR-9-2/3 double-mutant subpallium. The subpallium progenitor proliferation was enhanced, and the development of basal ganglia including striatum and globus pallidus was suppressed. Pallial/subpallial boundary shifted dorsally, and the ventral pallium was lost. Corridor was malformed, and thalamocortical and corticofugal axons were misrouted in the miR-9-2/3 double mutants.