Aggressive vertebral hemangiomas contain no adipose tissue resulting in thoracic spine kyphosis: A case report.

RATIONALE: Aggressive vertebral hemangiomas (AVHs) destroy continuous vertebral bodies and intervertebral discs and resulting in spinal kyphosis is extremely rare. The very aggressive behavior was attributable to its significant vascular component and contained no adipose tissue. PATIENT CONCERNS: We report a case of thoracic spine kyphosis of AVHs with multiple vertebral bodies and intervertebral disc destruction in a 45-year-old woman. DIAGNOSES: Based on the imaging studies, the patient underwent surgical removal of this lesion and spinal reconstruction. Histopathology consistent with vertebral hemangioma and contained no adipose. INTERVENTIONS: The patient underwent surgical removal of the lesion and spinal reconstruction. After subperiosteal dissection of the paraspinal muscles and exposure of the laminae, the laminae of the T5-7 vertebrae were removed and exposing the lesion. The lesion was soft and showed cystic changes, completely curetted and autogenous bone was implanted. Vertebroplasty was performed through T3-T9 pedicles bilaterally. Pedicle screw fixation was performed for segmental fixation and fusion. OUTCOMES: After 9 days of operation, the incision healed cleanly and free of pain. She was discharged in good general condition. The patient remained asymptomatic after follow-up 6 months of postoperative. LESSONS: AVHs destroy multiple vertebral bodies and intervertebral discs and resulting in spinal kyphosis is extremely rare.

Telecoupling between urban expansion and forest ecosystem service loss through cultivated land displacement: A case study of Zhejiang Province, China.

Urbanization can either directly occupy forests or indirectly lead to forest loss elsewhere through cultivated land displacement, resulting in further forest fragmentation and ecosystem service (ES) loss. However, the effects of urban expansion on forest area and ESs are unknown, and this is especially true for indirect effects. Taking Zhejiang Province, China, a typical deforested province, as an example, this study quantified the direct and indirect effects of urban expansion on forest area and five ESs (timber yield, water yield, carbon sequestration, soil conservation, and biodiversity) from 2000 to 2020, explored the relationship between forest structure (forest proportion, mean patch area, edge density, and mean euclidean nearest neighbor distance) change and ESs, and revealed the telecoupling of urban expansion and forest loss and cascade effects among urbanization, deforestation, forest structure, and ESs. The results indicated that the indirect forest loss (4.30%-6.15%) caused by cultivated land displacement due to urban expansion was larger than the direct forest loss (2.42%). Urban expansion has a greater negative impact on carbon sequestration (6.40%-8.20%), water yield (6.08%-7.78%), and biodiversity (5.79%-7.44%) than on timber yield (4.77%-6.17%) and soil conservation (4.43%-5.77%). The indirect forest ES loss was approximately 2.83-4.34 times greater than the direct forest ES loss. Most forest ESs showed a nonlinear significant positive correlation with changes in forest proportion and mean patch area and a significant nonlinear negative correlation with changes in edge density and mean Euclidean nearest neighbor distance (p < 0.05). There is telecoupling between urban expansion in one region and forest ES loss in other distant regions. This study contributes to guiding sustainable forest conservation and management globally.

Vegetation restoration thresholds under different vegetation types and altitude gradients in the Sichuan-Yunnan ecological shelter, China.

Determining the threshold for the response of ecosystem services (ESs) to vegetation change is critical for ecological restoration, and once the threshold is exceeded, ESs may be inhibited. Vegetation type and altitude are important factors affecting ESs. However, the nonlinear effects of vegetation change on ESs and their threshold under different vegetation types and altitude gradients are not clear. This study selected the Sichuan-Yunnan ecological shelter as the study area. Four ESs (water yield (WY), carbon storage (CS), soil conservation (SC), and water purification (WP)) were quantified by using the Integrated Valuation of Ecosystem Services and Trade-offs model. The differences in ESs among different vegetation types were identified. Variance analysis was used to explore the spatial differences in ESs under different altitude gradients. The inflection point of the promoting effect of vegetation cover on ESs was taken as the threshold, and elastic analysis was used to determine the impact threshold of fractional vegetation cover (FVC) on ESs. The threshold represents the inflection point at which vegetation cover promotes ESs. The results showed that the CS, SC, and WP of the natural forest were higher than those of the plantation, while the WY was lower than that of the plantation. WY, CS, and SC remained higher in the high-altitude regions, while nitrogen export was higher in the low-altitude regions. FVC was positively correlated with nitrogen export in the low-altitude regions and negatively correlated with WY in the high-altitude regions. FVC had a promoting effect on ESs, and the promoting effect was weakened beyond the threshold. The thresholds of FVC promoting ESs were 0.86, 0.79, 0.85, and 0.83 in natural forest, shrub, plantation, and grassland, respectively. The threshold of FVC promoting ESs in low-altitude regions was larger than that in high-altitude regions. This study can provide a theoretical basis for large-scale ecological management and moderate restoration.

Impacts of land use/land cover and soil property changes on soil erosion in the black soil region, China.

Soil erosion (SE) is seriously threatening grain production and the ecological environment in the black soil region. Understanding the impact of changes in land use/land cover (LULC) and soil properties on SE is critical for agricultural sustainability and soil management. However, the contribution of soil property changes to SE is often ignored in existing studies. This study analyzed changes in LULC and soil properties from 1980 to 2020 in the black soil region, China. Then, the revised universal soil loss equation was used to explore the spatiotemporal changes of SE from 1980 to 2020. Finally, the contribution of LULC change and soil property change to SE was separated by scenario comparison. The results showed that cropland increased (by 24,157 km2) at the expense of grassland and forest from 1980 to 2020. Sand in cropland decreased by 21.95%, while the silt, clay, and SOC increased by 21.37%, 1.43%, and 15.38%, respectively. Soil erodibility in cropland increased greatly (+9.85%), while in forest and grassland decreased (-6.05% and -4.72%). LULC change and soil properties change together aggravated SE in the black soil region. LULC change and soil property change resulted in a 22% increase in SE, of which LULC change resulted in a 14% increase, and soil property change resulted in an 8% increase. Agricultural development policy was the main reason driving LULC change. The combination of LULC change, climatic factors, and long-term tillage resulted in changes in soil properties. Ecosystem management and policy can reduce SE through vegetation restoration and soil improvement. This study can provide important references for soil conservation and agricultural development in the black soil region.

Exploring the spatiotemporal changes in carbon storage under different development scenarios in Jiangsu Province, China.

Carbon storage (CS) is closely linked to the global challenge of climate change. Land use/cover (LULC) change is the main factor driving changes in CS, and evaluating the impact of LULC changes on CS is important for carbon balance. Taking Jiangsu Province as an example, we used the Integrated Valuation of Ecosystem Services and Trade-offs model to analyze the spatiotemporal changes in CS during 2000-2015. Then we coupled it with the patch-generating land use simulation model to simulate and predict LULC and CS in 2050 under four different development plans. The results showed that LULC change in Jiangsu Province was manifested mainly as transformation of cropland to construction land (3,485 km2) and cropland to water body (470 km2). The high value area for CS was concentrated mainly in forest land, water body and grassland, whereas the low value area was concentrated mainly in construction land. During 2000-2015, CS decreased by 0.23 Tg, and during 2015-2050, CS was predicted to decrease by 0.16, 1.69, 0.02, and 0.10 Tg under the baseline, fast, slow and harmonious development scenarios. The conversion of a large amount of cropland to construction land was the main cause of CS loss. In all scenarios, the carbon loss was the largest in southern Jiangsu and lowest in central Jiangsu. It is necessary to balance the conflict between economic development and ecological protection during the process of urbanization. This study can provide an important reference for decision makers during the formulation of regional development models and ecological management strategies.

Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation.

The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.

Using high-resolution remote sensing images to explore the spatial relationship between landscape patterns and ecosystem service values in regions of urbanization.

Urbanization has substantially changed landscape patterns and seriously disturbed the structure and function of the ecosystems. However, the spatial characteristics and relationships between landscape patterns and ecosystem service values (ESVs) along the urban-rural gradient remain unclear. Based on high-resolution images, this study used concentric buffer zones to explore the characteristics and relationship between landscape pattern indexes (LPIs) and ESVs in the rural-urban gradient to reveal the impact of urban development on urban ecosystems. The results showed that the landscape heterogeneity was high in the urban fringe 18-20 km from the urban center. The PD, ED, LSI, SHAPE_MN, DIVISION, SPLIT, and SHIDI variables had the lowest values in the urban center, while CONTAG and AI had the high values in the urban. Water bodies and forest land are the main land use/land cover (LULC) types that provide ecosystem services. The total ESV of Kunshan city totaled 5597.31 × 106 CNY in 2018. The average ESV increased from 2.42 × 106 CNY to 9.92 × 106 CNY along the urban-rural gradient, which indicated that natural landscapes had higher ESVs. ED and Landscape Division Index (DIVISION) had positive effects on ESV, while Largest Patch Index (LPI), Contagion (CONTAG), Proportion of Like Adjacencies (PLADJ), Patch Cohesion Index (COHESION), and Aggregation Index (AI) had negative effects on ESV. The results of the regression model indicated there were quantitative relationships between ESVs and LPIs, which revealed how landscape pattern affected ESVs. The study can provide a scientific reference for the optimization of urban landscape patterns and urban and rural sustainable development.

Simulating the Impact of Future Climate Change and Ecological Restoration on Trade-Offs and Synergies of Ecosystem Services in Two Ecological Shelters and Three Belts in China.

Development of suitable ecological protection and restoration policies for sustainable management needs to assess the potential impacts of future land use and climate change on ecosystem services. The two ecological shelters and three belts (TSTB) are significant for improving ecosystem services and ensuring China's and global ecological security. In this study, we simulated land use in 2050 and estimated the spatial distribution pattern of net primary productivity (NPP), water yield, and soil conservation from 2010 to 2050 under future climate change. The results showed that water yield, NPP, and soil conservation exhibited a spatial pattern of decreasing from southeast to northwest, while in terms of the temporal pattern, water yield and NPP increased, but soil conservation decreased. Water yield was mainly influenced by precipitation, NPP was affected by temperature and implementation of ecological restoration, and soil conservation was controlled by precipitation and slope. There was a strong spatial heterogeneity between trade-offs and synergies. In terms of the temporal, with the combination of climate change and ecological restoration, there was a synergistic relationship between water yield and NPP. However, the relationships between water yield and soil conservation, and between NPP and soil conservation were characterized by trade-offs. In the process of ecological construction, it is necessary to consider the differences between overall and local trade-offs and synergies, as well as formulate sustainable ecological management policies according to local conditions. Understanding the response of ecosystem services to future climate change and land use policies can help address the challenges posed by climate change and achieve sustainable management of natural resources.

Preparation, Structure and Properties of Acid Aqueous Solution Plasticized Thermoplastic Chitosan.

This work provides a simple method for the preparation of thermoplastic chitosan using the most common dilute inorganic and organic acids in aqueous solutions, namely hydrochloric acid (HCl) and acetic acid (HAc). The melting plasticization behavior of chitosan under different concentrations and types of acid solution was investigated. By means of infrared spectra (IR), scanning electron microscope (SEM), X-ray diffraction (XRD), and other characterization methods, as well as a mechanical property test, it was found that as the acid solution concentration increased, the protonation effect was stronger and the plasticization performance showed a better trend. The structure and performance of the modified chitosan were optimal when the concentration of HCl was around 8 wt %. In addition, it was found that HCl had a better effect on the plasticization of chitosan than HAc, which was because the protonation ability of HCl was stronger than that of HAc. Unlike the casting method, the structure and properties of chitosan sheets prepared by thermoplastic processing were directly affected by protonation, however not by the interaction of anionic-cationic electrostatic attractions between the -NH3+ groups of chitosan chains and the carboxyl groups of acetic acids or the chloridoid groups of hydrochloric acid.

SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis.

Migration of placental extravillous trophoblast (EVT) cells into uterine decidua facilitates the establishment of blood circulation between mother and fetus and is modulated by EVT-decidual cell interaction. Poor or excessive EVT migration is associated with pregnancy complications such as preeclampsia or placenta accreta. Glial cells missing 1 (GCM1) transcription factor is essential for placental development, and decreased GCM1 activity is detected in preeclampsia. To study whether GCM1 regulates trophoblast cell migration, here we showed that GCM1 promotes BeWo and JAR trophoblast cell migration through a novel target gene, WNT10B. Moreover, WNT10B signaling stimulated cytoskeletal remodeling via Rac1 and frizzled 7 (FZD7) was identified as the cognate receptor for WNT10B to up-regulate cell migration. We further showed that secreted frizzled-related protein 3 (SFRP3) is expressed in uterine decidual cells by immunohistochemistry and that SFRP3 expression in telomerase-transformed human endometrial stromal cells (T-HESCs) is elevated under decidualization stimuli and further enhanced by bone morphogenetic protein 2 via SMAD1. SFRP3 blocked the interaction between FZD7 and WNT10B to decrease BeWo cell migration, which corroborated the elevated BeWo cell migration when cocultured with decidualized and SFRP3-knockdown T-HESC monolayer. Our results suggest that GCM1 up-regulates EVT cell migration through WNT10B and FZD7, which is negatively modulated by decidual SFRP3.-Wang, L.-J., Lo, H.-F., Lin, C.-F., Ng, P.-S., Wu, Y.-H., Lee, Y.-S., Cheong, M.-L., Chen, H. SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis.

New insights into the regulation of placental growth factor gene expression by the transcription factors GCM1 and DLX3 in human placenta.

Expression of placental growth factor (PGF) is closely associated with placental perfusion in early pregnancy. PGF is primarily expressed in placental trophoblasts, and its expression decreases in preeclampsia, associated with placental hypoxia. The transcription factors glial cells missing 1 (GCM1) and metal-regulatory transcription factor 1 (MTF1) have been implicated in the regulation of PGF gene expression through regulatory elements upstream and downstream of the PGF transcription start site, respectively. Here, we clarified the mechanism underlying placenta-specific PGF expression. We demonstrate that GCM1 up-regulates PGF expression through three downstream GCM1-binding sites (GBSs) but not a previously reported upstream GBS. Interestingly, we also found that these downstream GBSs also harbor metal-response elements for MTF1. Surprisingly, however, we observed that MTF1 is unlikely to regulate PGF expression in the placenta because knockdown or overexpression of GCM1, but not MTF1, dramatically decreased PGF expression or reversed the suppression of PGF expression under hypoxia, respectively. We also demonstrate that another transcription factor, Distal-less homeobox 3 (DLX3), interacts with the DNA-binding domain and the first transactivation domain of GCM1 and that this interaction inhibits GCM1-mediated PGF expression. Moreover, the GCM1-DLX3 interaction interfered with CREB-binding protein-mediated GCM1 acetylation and activation. In summary, we have identified several GBSs in the PGF promoter that are highly responsive to GCM1, have demonstrated that MTF1 does not significantly regulate PGF expression in placental cells, and provide evidence that DLX3 inhibits GCM1-mediated PGF expression. Our findings revise the mechanism for GCM1- and DLX3-mediated regulation of PGF gene expression.

Global quantitative proteomic analysis profiles host protein expression in response to Sendai virus infection.

Sendai virus (SeV) is an enveloped nonsegmented negative-strand RNA virus that belongs to the genus Respirovirus of the Paramyxoviridae family. As a model pathogen, SeV has been extensively studied to define the basic biochemical and molecular biologic properties of the paramyxoviruses. In addition, SeV-infected host cells were widely employed to uncover the mechanism of innate immune response. To identify proteins involved in the SeV infection process or the SeV-induced innate immune response process, system-wide evaluations of SeV-host interactions have been performed. cDNA microarray, siRNA screening and phosphoproteomic analysis suggested that multiple signaling pathways are involved in SeV infection process. Here, to study SeV-host interaction, a global quantitative proteomic analysis was performed on SeV-infected HEK 293T cells. A total of 4699 host proteins were quantified, with 742 proteins being differentially regulated. Bioinformatics analysis indicated that regulated proteins were mainly involved in "interferon type I (IFN-I) signaling pathway" and "defense response to virus," suggesting that these processes play roles in SeV infection. Further RNAi-based functional studies indicated that the regulated proteins, tripartite motif (TRIM24) and TRIM27, affect SeV-induced IFN-I production. Our data provided a comprehensive view of host cell response to SeV and identified host proteins involved in the SeV infection process or the SeV-induced innate immune response process.

Association of dysfunctional synapse defective 1 (SYDE1) with restricted fetal growth - SYDE1 regulates placental cell migration and invasion.

The transcription factor glial cells missing 1 (GCM1) regulates trophoblast differentiation and function during placentation. Decreased GCM1 expression is associated with pre-eclampsia, suggesting that abnormal expression of GCM1 target genes may contribute to the pathogenesis of pregnancy complications. Here we identified a novel GCM1 target gene, synapse defective 1 (SYDE1), which encodes a RhoGAP that is highly expressed in human placenta, and demonstrated that SYDE1 promotes cytoskeletal remodelling and cell migration and invasion. Importantly, genetic ablation of murine Syde1 results in small fetuses and placentas with aberrant phenotypes in the placental-yolk sac barrier, maternal-trophoblast interface, and placental vascularization. Microarray analysis revealed altered expression of renin-1, angiotensin I converting enzyme 2, angiotensin II type 1a receptor, and membrane metalloendopeptidase of the renin-angiotensin system in Syde1-knockout placenta, which may compensate for the vascular defects to maintain normal blood pressure. As pregnancy proceeds, growth restriction of the Syde1-/- fetuses and placentas continues, with elevated expression of the Syde1 homologue Syde2 in placenta. Syde2 may compensate for the loss of Syde1 function because SYDE2, but not the GAP-dead SYDE2 mutant, reverses migration and invasion activities of SYDE1-knockdown JAR trophoblast cells. Clinically, we further detected decreased SYDE1 expression in preterm and term IUGR placentas compared with gestational age-matched controls. Our study suggests a novel mechanism for GCM1 and SYDE1 in regulation of trophoblast cell migration and invasion during placental development and that decreased SYDE1 expression is associated with IUGR. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGß Expression and Cell Differentiation.

Human chorionic gonadotropin (hCG) is composed of a common α subunit and a placenta-specific ß subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCGß expression, it remains unclear how cAMP stimulates placenta-specific hCGß gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCGß paralogues by chromatin immunoprecipitation-on-chip (ChIP-chip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCGß promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCGß promoter and GCM1 but not TFAP2C. Indeed, the hCG-cAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGß expression and cell differentiation.

Cyclin D1 acts as a barrier to pluripotent reprogramming by promoting neural progenitor fate commitment.

A short G1 phase is a characteristic feature of the cell cycle structure of pluripotent cells, and is reestablished during Yamanaka factor-mediated pluripotent reprogramming. How cell cycle control is adjusted to meet the requirements of pluripotent cell fate commitment during reprogramming is less well understood. Elevated levels of cyclin D1 were initially found to impair pluripotency maintenance. The current work further identified Cyclin D1 to be capable of transcriptionally upregulating Pax6, which promoted reprogramming cells to commit to a neural progenitor fate rather than a pluripotent cell fate. These findings explain the importance of reestablishment of G1-phase restriction in pluripotent reprogramming.

A role for interleukin-17A in modulating intracellular survival of Mycobacterium bovis bacillus Calmette-Guérin in murine macrophages.

Interleukin 17A IL-17A is a crucial immunomodulator in various chronic immunological diseases including rheumatoid arthritis and inflammatory bowel disease. The cytokine has also been demonstrated to control the pathogenesis of the Mycobacterium tuberculosis by dysregulating production of cytokines and chemokines and promoting granuloma formation. Whether IL-17A regulates innate defence mechanisms of macrophages in response to mycobacterial infection remains to be elucidated. In the current report, we investigated the effects of IL-17A on modulating the intracellular survival of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in RAW264.7 murine macrophages. We observed that IL-17A pre-treatment for 24 hr was able to synergistically enhance BCG-induced nitric oxide (NO) production and inducible nitric oxide synthase expression in dose- and time-dependent manners. We further delineated the mechanisms involved in this synergistic reaction. IL-17A was found to specifically enhanced BCG-induced phosphorylation of Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. By using a specific JNK inhibitor (SP600125), we found that the production of NO in BCG-infected macrophages was significantly suppressed. Taken together, we confirmed the involvement of the JNK pathway in IL-17A-enhanced NO production in BCG-infected macrophages. We further demonstrated that IL-17A significantly enhanced the clearance of intracellular BCG by macrophages through an NO-dependent killing mechanism. In conclusion, our study revealed an anti-mycobacterial role of IL-17A through priming the macrophages to produce NO in response to mycobacterial infection.

High-temperature requirement protein A4 (HtrA4) suppresses the fusogenic activity of syncytin-1 and promotes trophoblast invasion.

Cell-cell fusion and cell invasion are essential for placental development. Human cytotrophoblasts in the chorionic villi may undergo cell-cell fusion to form syncytiotrophoblasts to facilitate nutrient-gas exchange or differentiate into extravillous trophoblasts (EVTs) to facilitate maternal-fetal circulation. The placental transcription factor glial cells missing 1 (GCM1) regulates syncytin-1 and -2 expression to mediate trophoblast fusion. Interestingly, GCM1 and syncytin-1 are also expressed in EVTs with unknown physiological functions. In this study, we performed chromatin immunoprecipitation-on-chip (ChIP-chip) analysis and identified the gene for high-temperature requirement protein A4 (HtrA4) as a GCM1 target gene, which encodes a serine protease facilitating cleavage of fibronectin and invasion of placental cells. Importantly, HtrA4 is immunolocalized in EVTs at the maternal-fetal interface, and its expression is decreased by hypoxia and in preeclampsia, a pregnancy complication associated with placental hypoxia and shallow trophoblast invasion. We further demonstrate that HtrA4 interacts with syncytin-1 and suppresses cell-cell fusion. Therefore, HtrA4 may be crucial for EVT differentiation by playing a dual role in prevention of cell-cell fusion of EVTs and promotion of their invasion into the uterus. Our study reveals a novel function of GCM1 and HtrA4 in regulation of trophoblast invasion and that abnormal HrtA4 expression may contribute to shallow trophoblast invasion in preeclampsia.

GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta.

Syncytin 2 is a newly identified placental membrane protein with fusogenic and immunosuppressive activities. Major facilitator superfamily domain containing 2A (MFSD2A) is the cognate receptor for syncytin 2-mediated cell-cell fusion. Both syncytin 2 and MFSD2A are highly expressed in placenta. In this study to understand the regulation of syncytin 2 and MFSD2A expression in placenta, we found that syncytin 2 gene is epigenetically silenced in nonplacental cells by cytosine-phosphate-guanine (CpG) dinucleotide methylation and that expression of syncytin 2 and MFSD2A genes are regulated by the placental transcription factor GCM1 in placental cells. Functional GCM1-binding sites were identified in syncytin 2 and MFSD2A promoters based on electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Because GCM1 activity is decreased in hypoxic placental cells, we further confirmed that expression of MFSD2A is downregulated in hypoxic BeWo choriocarcinoma cells. Interestingly, ectopic expression of GCM1 activated syncytin 2 and MFSD2A expression in MCF-7 breast cancer cells and facilitated MCF-7 cell fusion. The expression of syncytin 2 in MCF-7 cells was partly attributed to CpG demethylation in the syncytin 2 promoter in the presence of GCM1. Our results suggest that GCM1 is a critical factor in controlling placental cell fusion through transcriptional regulation of syncytin 2 and MFSD2A gene expression in placenta. In addition, GCM1 may also play an important role in the epigenetic regulation of syncytin 2 gene expression.

Mechanism of hypoxia-induced GCM1 degradation: implications for the pathogenesis of preeclampsia.

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-3beta activation. Activated GSK-3beta phosphorylates GCM1 on Ser322, which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3beta 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.