Parchem Ronald J, Moore Nicole, Fish Jennifer L, Parchem Jacqueline G, Braga Tarcio T, Shenoy Archana, Oldham Michael C, Rubenstein John L R, Schneider Richard A, Blelloch Robert
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell Rep. 2015 Aug 4;12(5):760-73. doi: 10.1016/j.celrep.2015.06.074. Epub 2015 Jul 23.
The evolutionarily conserved miR-302 family of microRNAs is expressed during early mammalian embryonic development. Here, we report that deletion of miR-302a-d in mice results in a fully penetrant late embryonic lethal phenotype. Knockout embryos have an anterior neural tube closure defect associated with a thickened neuroepithelium. The neuroepithelium shows increased progenitor proliferation, decreased cell death, and precocious neuronal differentiation. mRNA profiling at multiple time points during neurulation uncovers a complex pattern of changing targets over time. Overexpression of one of these targets, Fgf15, in the neuroepithelium of the chick embryo induces precocious neuronal differentiation. Compound mutants between mir-302 and the related mir-290 locus have a synthetic lethal phenotype prior to neurulation. Our results show that mir-302 helps regulate neurulation by suppressing neural progenitor expansion and precocious differentiation. Furthermore, these results uncover redundant roles for mir-290 and mir-302 early in development.
进化上保守的微小RNA miR - 302家族在哺乳动物早期胚胎发育过程中表达。在此，我们报告小鼠中miR - 302a - d的缺失导致完全显性的晚期胚胎致死表型。基因敲除胚胎存在与神经上皮增厚相关的前神经管闭合缺陷。神经上皮显示祖细胞增殖增加、细胞死亡减少和神经元过早分化。在神经胚形成过程中的多个时间点进行的mRNA谱分析揭示了随着时间变化的复杂靶标模式。这些靶标之一Fgf15在鸡胚神经上皮中的过表达诱导了神经元过早分化。mir - 302与相关的mir - 290基因座之间的复合突变体在神经胚形成之前具有合成致死表型。我们的结果表明，mir - 302通过抑制神经祖细胞扩增和过早分化来帮助调节神经胚形成。此外，这些结果揭示了mir - 290和mir - 302在发育早期的冗余作用。
