Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies worldwide. Although hypoxia caused by incomplete trophoblast invasion and impaired spiral arterial remodeling is thought to be a major cause of preeclampsia, how hypoxia affects placental development remains uncertain. GCM1 (glial cells missing homolog 1) is a transcription factor critical for placental development. In preeclampsia, GCM1 and its target genes syncytin 1 and placental growth factor, important for syncytiotrophoblast formation and placental vasculogenesis, are all decreased. Here we present evidence that GCM1 is a major target of hypoxia associated with preeclampsia. We show that hypoxia triggers GCM1 degradation by suppressing the phosphatidylinositol 3-kinase-Akt signaling pathway, leading to GSK-3 activation. Activated GSK-3 phosphorylates GCM1 on Ser 322 , which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3 inhibitor LiCl prevented hypoxia-induced GCM1 degradation. Our study identifies a molecular basis for the disrupted GCM1 transcription network in preeclampsia and provides a potential avenue for therapeutic intervention.Trophoblast invasion, fetoplacental vascular development, and maternal vascular remodeling are key events for the formation of the hemochorial placenta in humans. Human placental trophoblasts make direct contact with maternal blood to mediate efficient gas and nutrient exchange between mother and fetus. It is evident that failure in the aforementioned key events will compromise placental function and have a significant impact on the health of both fetus and mother. Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies worldwide. The clinical features of preeclampsia include hypertension, proteinuria, and edema. Although the etiologic factors of preeclampsia are currently unknown, shallow trophoblast invasion and poor maternal vascular remodeling have been reported in preeclamptic placentas. It is thought that these defects impair the development of the fetal-maternal vasculature and result in placental ischemia and hypoxia, which contribute to the pathogenesis of preeclampsia (1-3). Consistent with this model, expression of the antiangiogenic protein soluble Flt-1 (Fms-like tyrosine kinase-1) (sFlt-1) 3 is elevated, whereas expression of the proangiogenic vascular endothelial growth factor (VEGF) and placental growth factor (PGF) is decreased in preeclampsia (4, 5). Systematic surveys of pregnant women have further revealed that the ratio between the circulating levels of sFlt-1 and PGF increases significantly prior to the onset of preeclampsia (6, 7). Therefore, an imbalance between pro-and antiangiogenic factors may be a contributing factor in preeclampsia pathogenesis.GCM1 (also known as GCMa) is a key transcription factor in placental development. Genetic ablation of mouse GCM1 is embryonically lethal due to failure of the formation of the labyrinth layer and the fusion of trophoblasts to syncyti...
Glial cell missing homolog 1 (GCM1) is an important transcription factor regulating placental cell fusion. Recently, we have demonstrated that GCM1 is a labile protein and that the F-box protein FBXW2 (F-box and WD repeat domain containing 2) mediates GCM1 ubiquitination for proteasomal degradation. Multiple factors are involved in the ubiquitin-proteasome degradation system. Therefore, in order to better understand the mechanism regulating GCM1 stability, we further isolated and characterized the E2 ubiquitin-conjugating enzyme responsible for FBXW2-mediated ubiquitination of GCM1 in this study. We prepared and screened a variety of E2 proteins in an in vitro ubiquitination assay system for GCM1 and found that UBE2D2 is required for the SCF(FBXW2) E3 ligase in regulation of GCM1 ubiquitination. We also demonstrated that the enzyme activity of UBE2D2 is required for GCMa ubiquitination and for association with the SCF(FBXW2) complex. Moreover, knocking down UBE2D2 expression by RNA interference not only suppressed FBXW2-mediated GCM1 ubiquitination, but also prolonged the half-life of GCM1 in vivo. Our results suggest that UBE2D2 is a functional E2 protein which, together with FBXW2, regulates GCM1 stability in the placenta.
While many monocular depth estimation methods have been proposed, determining depth variations in outdoor scenes remains challenging. Accordingly, this paper proposes an image segmentation-based monocular depth estimation model with attention mechanisms that can address outdoor scene variations. The segmentation model segments images into foreground and background regions and individually predicts depth maps. Moreover, attention mechanisms are also adopted to extract meaningful features from complex scenes to improve foreground and background depth map prediction via a multi-scale decoding scheme. From our experimental results, we observed that our proposed model outperformed previous methods by 27.5% on the KITTI dataset.
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