Mouillet Jean-Francois, Goff Julie, Sadovsky Elena, Sun Huijie, Parks Tony, Chu Tianjiao, Sadovsky Yoel
Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Placenta. 2020 Nov;101:208-214. doi: 10.1016/j.placenta.2020.09.069. Epub 2020 Sep 29.
The chromosome 19 miRNA cluster (C19MC) encodes a large family of microRNAs (miRNAs) that are abundantly expressed in the placenta of higher primates and also in certain cancers. In the placenta, miRNAs from this cluster account for nearly 40% of all miRNAs present in trophoblasts. However, the function of these miRNAs in the placenta remains poorly understood. Recent observations reveal a role for these miRNAs in cell migration, and suggest that they are involved in the development and function of the human placenta. Here, we examine the placenta in transgenic mice expressing the human C19MC miRNAs.
We produced transgenic mice using pronuclear microinjection of a bacterial artificial chromosome plasmid carrying the entire human C19MC locus and derived a homozygous line using crossbreeding. We performed morphological characterization and profiled gene expression changes in the placentas of the transgenic mice.
C19MC transgenic mice delivered on time with no gross malformations. The placentas of transgenic mice expressed C19MC miRNAs and were larger than wild type placentas. Histologically, we found that the transgenic placenta exhibited projections of spongiotrophoblasts that penetrated deep into the labyrinth. Gene expression analysis revealed alterations in the expression of several genes involved in cell migration, with evidence of enhanced cell proliferation.
Mice that were humanized for transgenically overexpressed C19MC miRNAs exhibit enlarged placentas with aberrant delineation of cell layers. The observed phenotype and the related gene expression changes suggest disrupted migration of placental cell subpopulations.
19号染色体微小RNA簇（C19MC）编码一大类微小RNA（miRNA），这些微小RNA在高等灵长类动物的胎盘中大量表达，在某些癌症中也有表达。在胎盘中，来自该簇的微小RNA占滋养层细胞中所有微小RNA的近40%。然而，这些微小RNA在胎盘中的功能仍知之甚少。最近的观察结果揭示了这些微小RNA在细胞迁移中的作用，并表明它们参与了人类胎盘的发育和功能。在这里，我们研究了表达人类C19MC微小RNA的转基因小鼠的胎盘。
我们通过原核显微注射携带整个人类C19MC基因座的细菌人工染色体质粒来制备转基因小鼠，并通过杂交获得纯合品系。我们对转基因小鼠胎盘进行了形态学表征并分析了基因表达变化。
C19MC转基因小鼠按时分娩，无明显畸形。转基因小鼠的胎盘表达C19MC微小RNA，且比野生型胎盘大。组织学上，我们发现转基因胎盘表现出海绵滋养层细胞的突起，这些突起深入到迷路中。基因表达分析显示，参与细胞迁移的几个基因的表达发生了改变，有细胞增殖增强的证据。
转基因过表达C19MC微小RNA的人源化小鼠表现出胎盘增大，细胞层界限异常。观察到的表型和相关基因表达变化表明胎盘细胞亚群的迁移受到破坏。
