ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

Abstract

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. Cell Death and Differentiation (2015) 22, 1970-1984 doi:10.1038/cdd.2015 published online 24 April 2015 In mammalian development, the placenta forms the mechanical and physiological link between maternal and fetal circulations. In rodents and higher order primates, including humans, this transfer is achieved through extensive uterine infiltration by fetal-derived cells of epithelial lineage called trophoblasts.1 Trophoblast differentiation is essential for optimal placental function, where the underlying molecular processes regulating specific functions of distinct trophoblast populations are strictly controlled. Defects in trophoblast differentiation associate with impaired placental function and directly impact fetal and maternal health. Within the placenta, progenitor trophoblasts (also called villous cytotrophoblasts; vCTs) overlie a well-defined basal lamina forming an organized, mitotically active epithelial layer. vCT differentiation into an overlying multinucleated structure called the syncytiotrophoblast (synCT) is a key event in placental development. 3 The synCT, composed of millions of nuclei sharing one common cytoplasm, directs nutrient and gas exchange between m...

Dual control of pcdh8l/PCNS expression and function in Xenopus laevis neural crest cells by adam13/33 via the transcription factors tfap2α and arid3a

“…Similarly, the observed role of adam12 in mediating TGF-β signaling, may involve an interaction with arid3a, a protein known to be downstream of the TGF-β effector Smad2 ( Callery et al, 2005 ). The fact that both adam12 and arid3a are critical for trophoblast formation ( Rhee et al, 2017 ; Aghababaei et al, 2015 ; Rhee et al, 2014 ; Aghababaei et al, 2014 ) suggests that this functional interaction may be important in multiple cell types to mediate key developmental processes.…”

Low oxygen enhances trophoblast column growth by potentiating differentiation of the extravillous lineage and promoting LOX activity

“…Tissues were paraffin embedded and sectioned at 6 µm onto glass slides. Immunofluorescence was performed as described elsewhere (Aghababaei et al, 2015). Briefly, cells or placental tissues underwent antigen retrieval by heating slides in a microwave for 5×2 min intervals in a citrate buffer ( pH 6.0).…”

Brown Seaweed Fucoidan Inhibits Cancer Progression by Dual Regulation of mir-29c/ADAM12 and miR-17-5p/PTEN Axes in Human Breast Cancer Cells

“…ADAM12 is a member of the metalloproteinase-disintegrin family and a breast cancer-associated gene. ADAM12 expression is strongly upregulated in preinvasive and invasive carcinomas 19-23. In addition, miR-29b/c and miR-200b/c post-transcriptionally mediate the downregulation of ADAM12 by directly targeting the 3'-UTR of ADAM12, resulting in degradation or decreased translation of target mRNAs.…”