title: Where polarity meets fusion: role of Par6 in trophoblast differentiation during placental development and preeclampsia.
abstract: Trophoblast cell fusion is a prerequisite for proper human placental development. Herein we examined the contribution of Par6 (Partitioning defective protein 6), a key regulator of cell polarity, to trophoblast cell fusion in human placental development. During early placentation, Par6 localized to nuclei of cytotrophoblast cells but with advancing gestation Par6 shifted its localization to the cytoplasm and apical brush border of the syncytium. Exposure of primary isolated trophoblasts to 3% O(2) resulted in elevated Par6 expression, maintenance of tight junction marker ZO-1 at cell boundaries, and decreased fusogenic syncytin 1 expression compared with cells cultured at 20% O(2). Treatment of choriocarcinoma BeWo cells with forskolin, a known inducer of fusion, increased syncytin 1 expression but decreased that of Par6 and ZO-1. Par6 overexpression in the presence of forskolin maintained ZO-1 at cell boundaries while decreasing syncytin 1 levels. In contrast, silencing of Par6 disrupted ZO-1 localization at cell boundaries and altered the expression and distribution of acetylated α-tubulin. Par6 expression was elevated in preeclamptic placentas relative to normotensive preterm controls and Par6 located to trophoblast cells expressing ZO-1. Together, our data indicate that Par6 negatively regulates trophoblast fusion via its roles on tight junctions and cytoskeleton dynamics and provide novel insight into the contribution of this polarity marker in altered trophoblast cell fusion typical of preeclampsia.
authors: Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada M5T 3H7.
authors: Tharini
authors: T
authors: Sivasubramaniyam
authors: Julia
authors: J
authors: Garcia
authors: Andrea
authors: A
authors: Tagliaferro
authors: Megan
authors: M
authors: Melland-Smith
authors: Sarah
authors: S
authors: Chauvin
authors: Martin
authors: M
authors: Post
authors: Tullia
authors: T
authors: Todros
authors: Isabella
authors: I
authors: Caniggia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology; D005260:Female; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D008561:Membrane Fusion / Q000502:physiology; D008954:Models, Biological; D010920:Placenta / Q000473:pathology / Q000503:physiopathology; D010929:Placentation / Q000502:physiology; D011225:Pre-Eclampsia / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D034741:RNA, Small Interfering / Q000235:genetics; D014327:Trophoblasts / Q000166:cytology* / Q000502:physiology*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C499657:PARD6A protein, human; D034741:RNA, Small Interfering; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein