MiR-302/367 regulate neural progenitor proliferation, differentiation timing, and survival in neurulation.
MiR-302/367 regulate neural progenitor proliferation, differentiation timing, and survival in neurulation.
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DOI：
10.1016/j.ydbio.2015.09.020
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发表时间：
2015-12-01
影响因子：
2.7
通讯作者：
Chen JF
中科院分区：
文献类型：
--
作者：
Yang SL;Yang M;Herrlinger S;Liang C;Lai F;Chen JF
神经祖细胞（NPC）的行为在早期发育的胚胎中是如何被暂时控制的，目前还不清楚。microRNA（miRNAs）在哺乳动物早期发育中的体内功能仍然是未知的。Mir-302/367是编码miR-367和四个miR-302成员（miR 302 a-d）的miRNA簇。我们发现，miR-302 b在早期神经上皮中高度表达，其表达随着发育的进展而下降。我们建立了mir-302/367基因敲除小鼠模型，发现mir-302/367的缺失导致早期胚胎死亡和开放性神经管缺陷（NTD）。NPC在突变胚胎中表现出增强的增殖、早熟分化和降低的细胞存活。此外，我们发现Fgf 15、Cyclin D1和D2是体内NPC中miR-302的直接靶点，并且它们的表达在突变NPC中增强。细胞周期蛋白D1和D2的异位表达增加了NPC的增殖，而FGF 19（Fgf 15的人类直系同源物）的过表达导致NPC分化的增加。因此，这些发现揭示了miR-302/367在神经形成中协调基因表达和NPC行为的重要作用;它们还指出miRNA是与神经管形成相关的关键遗传组分。
How neural progenitor cell (NPC) behaviors are temporally controlled in early developing embryos remains undefined. The in vivo functions of microRNAs (miRNAs) in early mammalian development remain largely unknown. Mir-302/367 is a miRNA cluster that encodes miR-367 and four miR-302 members (miR302a-d). We show that miR-302b is highly expressed in early neuroepithelium and its expression decline as development progresses. We generated a mir-302/367 knockout mouse model and found that deletion of mir-302/367 results in an early embryonic lethality and open neural tube defect (NTD). NPCs exhibit enhanced proliferation, precocious differentiation, and decreased cell survival in mutant embryos. Furthermore, we identified Fgf15, Cyclin D1, and D2 as direct targets of miR-302 in NPCs in vivo, and their expression is enhanced in mutant NPCs. Ectopic expression of Cyclin D1 and D2 increases NPC proliferation, while FGF19 (human ortholog of Fgf15) overexpression leads to an increase of NPC differentiation. Thus, these findings reveal essential roles of miR-302/367 in orchestrating gene expression and NPC behaviors in neurulation; they also point to miRNAs as critical genetic components associated with neural tube formation.