Grandjean Valérie, Gounon Pierre, Wagner Nicole, Martin Luc, Wagner Kay D, Bernex Florence, Cuzin François, Rassoulzadegan Minoo
Inserm U636, F-06108 Nice, France.
Development. 2009 Nov;136(21):3647-55. doi: 10.1242/dev.041061.
The size of the mammalian body is determined by genetic and environmental factors differentially modulating pre- and postnatal growth. We now report a control of growth acting in the mouse from the first cleavages to the postnatal stages. It was evidenced by a hereditary epigenetic modification (paramutation) created by injection of a miR-124 microRNA into fertilized eggs. From the blastocyst to the adult, mouse pups born after microinjection of this miRNA showed a 30% increase in size. At the blastocyst stage, frequent duplication of the inner cell mass resulted in twin pregnancies. A role of sperm RNA as a transgenerational signal was confirmed by the giant phenotype of the progeny of transgenic males expressing miR-124 during spermiogenesis. In E2.5 to E8.5 embryos, increased levels of several transcripts with sequence homology to the microRNA were noted, including those of Sox9, a gene known for its crucial role in the progenitors of several adult tissues. A role in embryonic growth was confirmed by the large size of embryos expressing a Sox9 DNA transgene. Increased expression in the paramutants was not related to a change in miR-124 expression, but to the establishment of a distinct, heritable chromatin structure in the promoter region of Sox9. While the heritability of body size is not readily accounted for by Mendelian genetics, our results suggest the alternate model of RNA-mediated heritable epigenetic modifications.
哺乳动物身体的大小由遗传和环境因素决定，这些因素以不同方式调节产前和产后生长。我们现在报告一种从第一次卵裂到产后阶段在小鼠中起作用的生长控制机制。这一机制通过向受精卵注射miR-124微小RNA所产生的一种遗传性表观遗传修饰（副突变）得以证明。从囊胚期到成年期，显微注射这种微小RNA后出生的小鼠幼崽体型增大了30%。在囊胚阶段，内细胞团频繁复制导致了双胎妊娠。精子RNA作为一种跨代信号的作用通过在精子发生过程中表达miR-124的转基因雄性后代的巨大表型得到了证实。在E2.5至E8.5胚胎中，发现了几种与该微小RNA具有序列同源性的转录本水平升高，包括Sox9的转录本，Sox9是一个在几种成年组织的祖细胞中起关键作用的基因。表达Sox9 DNA转基因的胚胎体型较大，证实了其在胚胎生长中的作用。副突变体中表达增加与miR-124表达的变化无关，而是与Sox9启动子区域中一种独特的、可遗传的染色质结构的建立有关。虽然体型的遗传性不容易用孟德尔遗传学来解释，但我们的结果提出了RNA介导的可遗传表观遗传修饰的替代模型。
