Aghababaei M, Hogg K, Perdu S, Robinson W P, Beristain A G
The Child & Family Research Institute, Vancouver, British Columbia, Canada.
Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, British Columbia, Canada.
Cell Death Differ. 2015 Dec;22(12):1970-84. doi: 10.1038/cdd.2015.44. Epub 2015 Apr 24.
Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development.
滋养层细胞是上皮谱系的胎盘细胞，会经历广泛分化以形成胎盘的细胞成分。滋养层祖细胞分化为多核合体滋养层细胞是胎盘功能所需的关键发育过程，其中合体滋养层细胞形成和更新的缺陷与胎盘病理相关，并与不良妊娠结局有关。目前对控制合体滋养层细胞形成的细胞和分子过程了解甚少，但这需要激活指导细胞融合的信号通路。蛋白酶“解整合素金属蛋白酶12”（ADAM12）可控制成肌细胞中的细胞融合，在胎盘中高度表达，定位于多个滋养层细胞群体。然而，ADAM12在调节滋养层细胞融合中的重要性尚不清楚。在此，我们描述了ADAM12在调节滋养层细胞融合中的作用。使用两种不同的滋养层细胞融合模型，我们发现ADAM12会动态上调，且受蛋白激酶A的转录调控。通过小干扰RNA敲低ADAM12会阻碍原代细胞滋养层细胞的自发融合，而分泌变体ADAM12S的过表达则会增强Bewo滋养层细胞系中的细胞融合。从机制上讲，异位和内源性水平的ADAM12均通过E-钙黏蛋白胞外域脱落和细胞间边界重塑来控制滋养层细胞融合。本研究描述了ADAM12在胎盘发育中的新作用，特别强调了其在控制绒毛细胞滋养层细胞分化为多核细胞结构中的重要性。此外，这项工作确定E-钙黏蛋白是一种新的ADAM12底物，并强调了细胞黏附分子胞外域脱落在正常发育中的重要性。
