The Hippo Signaling Pathway Components Lats and Yap Pattern Tead4 Activity to Distinguish Mouse Trophectoderm from Inner Cell Mass

Outside cells of the preimplantation mouse embryo form the trophectoderm (TE), a process requiring the transcription factor Tead4. Here, we show that transcriptionally active Tead4 can induce Cdx2 and other trophoblast genes in parallel in embryonic stem cells. In embryos, the Tead4 coactivator protein Yap localizes to nuclei of outside cells, and modulation of Tead4 or Yap activity leads to changes in Cdx2 expression. In inside cells, Yap is phosphorylated and cytoplasmic, and this involves the Hippo signaling pathway component Lats. We propose that active Tead4 promotes TE development in outside cells, whereas Tead4 activity is suppressed in inside cells by cell contact- and Lats-mediated inhibition of nuclear Yap localization. Thus, differential signaling between inside and outside cell populations leads to changes in cell fate specification during TE formation

Three T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen antigens, retain their immunogenicity and tolerogenicity in a linked peptide

It has been demonstrated in detail that administration of a dominant T-cell determinant to animals induces activation or immunological tolerance of T cells. However, it has not been determined whether multiple T-cell determinants, when integrated into a single peptide, retain their potential to induce T-cell activation and tolerance. We prepared a synthetic peptide comprising three T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen antigens, and investigated the immunogenicity and tolerogenicity of each T-cell determinant in the linked peptide by means of lymph node cell proliferation assays using mice. Lymph node cells from mice immunized with each of the three T-cell determinants proliferated against the linked peptide in a dose-dependent manner, similar to that of the immunized peptide. Lymph node cells from mice immunized with the linked peptide proliferated against all of the three T-cell determinants. In addition, the degree of proliferation against the three T-cell determinants occurred according to their original immunogenicity, as observed in the native protein antigens. Oral administration of the linked peptide to mice before they were immunized with Cry j 1 and Cry j 2 inhibited lymph node cell proliferation against the three T-cell determinants, depending on the dose of the linked peptide administered. In conclusion, it was demonstrated that three T-cell determinants retain their original immunogenicity and tolerogenicity in a linked peptide comprising them

Fabrication of a novel magnetic topological heterostructure and temperature evolution of its massive Dirac cone

Materials that possess nontrivial topology and magnetism is known to exhibit exotic quantum phenomena such as the quantum anomalous Hall effect. Here, we fabricate a novel magnetic topological heterostructure Mn4Bi2Te7/Bi2Te3 where multiple magnetic layers are inserted into the topmost quintuple layer of the original topological insulator Bi2Te3. A massive Dirac cone (DC) with a gap of 40–75 meV at 16 K is observed. By tracing the temperature evolution, this gap is shown to gradually decrease with increasing temperature and a blunt transition from a massive to a massless DC occurs around 200–250 K. Structural analysis shows that the samples also contain MnBi2Te4/Bi2Te3. Magnetic measurements show that there are two distinct Mn components in the system that corresponds to the two heterostructures; MnBi2Te4/Bi2Te3 is paramagnetic at 6 K while Mn4Bi2Te7/Bi2Te3 is ferromagnetic with a negative hysteresis (critical temperature ~20 K). This novel heterostructure is potentially important for future device applications.T.H. was supported by JSPS KAKENHI Grant Number 18H03877, the Murata Science Foundation (No. H30-084), the Asahi Glass Foundation, Tokyo Tech. Challenging Research Award, and the Iketani Science and Technology Foundation (No. 0321083-A). M.K. was supported by the Spintronics Research Network of Japan (Spin-RNJ). The ARPES measurements were performed under the UVSOR proposal Nos. 29-837, 30-571, 30-860 and the SARPES measurements were performed under the HiSOR proposal No. 16BG001. The XMCD measurements were performed at JAEA beamline BL-23SU in SPring-8 (Proposal No. 2018B3843) and also at PF-KEK (PF PAC No. 17P006). The work at SPring-8 was performed under the Shared Use Program of JAEA Facilities (Proposal No. 2018B-E21) with the approval of Nanotechnology Platform project supported by the Ministry of Education, Culture, Sports, Science and Technology (Proposal No. A-18-AE-0039). The support by Tomsk State University competitiveness improvement program (No. 8.1.01.2018), the Saint Petersburg State University (Project ID 51126254), the Russian Science Foundation (Grant No. 18-12-00169) and the Government research assignment for ISPMS SB RAS, project No. III.23.2.9 is gratefully acknowledged. M.M.O. acknowledges the support by Spanish Ministerio de Ciencia e Innovación (Grant No. PID2019-103910GB-I00).Peer reviewe

Polarity-Dependent Distribution of Angiomotin Localizes Hippo Signaling in Preimplantation Embryos

SummaryBackgroundIn preimplantation mouse embryos, the first cell fate specification to the trophectoderm or inner cell mass occurs by the early blastocyst stage. The cell fate is controlled by cell position-dependent Hippo signaling, although the mechanisms underlying position-dependent Hippo signaling are unknown.ResultsWe show that a combination of cell polarity and cell-cell adhesion establishes position-dependent Hippo signaling, where the outer and inner cells are polar and nonpolar, respectively. The junction-associated proteins angiomotin (Amot) and angiomotin-like 2 (Amotl2) are essential for Hippo pathway activation and appropriate cell fate specification. In the nonpolar inner cells, Amot localizes to adherens junctions (AJs), and cell-cell adhesion activates the Hippo pathway. In the outer cells, the cell polarity sequesters Amot from basolateral AJs to apical domains, thereby suppressing Hippo signaling. The N-terminal domain of Amot is required for actin binding, Nf2/Merlin-mediated association with the E-cadherin complex, and interaction with Lats protein kinase. In AJs, S176 in the N-terminal domain of Amot is phosphorylated by Lats, which inhibits the actin-binding activity, thereby stabilizing the Amot-Lats interaction to activate the Hippo pathway.ConclusionsWe propose that the phosphorylation of S176 in Amot is a critical step for activation of the Hippo pathway in AJs and that cell polarity disconnects the Hippo pathway from cell-cell adhesion by sequestering Amot from AJs. This mechanism converts positional information into differential Hippo signaling, thereby leading to differential cell fates

Induction of Sparc by Vegf in Human Vascular Endothelial Cells

SPARC/osteonectin/BM-40 is a matricellular protein that is thought to be involved in angiogenesis and endothelial barrier function. Previously, we have detected high levels of SPARC expression in endothelial cells (ECs) adjacent to carcinomas of kidney and tongue. Although SPARC-derived peptide showed an angiogenic effect, intact SPARC itself inhibited the mitogenic activity of vascular endothelial growth factor (VEGF) for ECs by the inhibiting phosphorylation of flt-1 (VEGF receptor 1) and subsequent ERK activation. Thus, the role of SPARC in tumor angiogenesis, stimulation or inhibition, is still unclear. To clarify the role of SPARC in tumor growth and progression, we determined the effect of VEGF on the expression of SPARC in human microvascular EC line, HMEC-1, and human umbilical vein ECs. VEGF increased the levels of SPARC protein and steady-state levels of SPARC mRNA in serum-starved HMEC-1 cells. Inhibitors (SB202190 and SB203580) of p38, a mitogen-activated protein (MAP) kinase, attenuated VEGF-stimulated SPARC production in ECs. Since intact SPARC inhibits phosphorylation ERK MAP kinase in VEGF signaling, it was suggested that SPARC plays a dual role in the VEGF functions, tumor angiogenesis, and extravasation of tumors mediated by the increased permeability of endothelial barrier function

Large-gap magnetic topological heterostructure formed by subsurface incorporation of a ferromagnetic layer

Inducing magnetism into topological insulators is intriguing for utilizing exotic phenomena such as the quantum anomalous Hall effect (QAHE) for technological applications. While most studies have focused on doping magnetic impurities to open a gap at the surface-state Dirac point, many undesirable effects have been reported to appear in some cases that makes it difficult to determine whether the gap opening is due to the time-reversal symmetry breaking or not. Furthermore, the realization of the QAHE has been limited to low temperatures. Here we have succeeded in generating a massive Dirac cone in a MnBiSe/BiSe heterostructure, which was fabricated by self-assembling a MnBiSe layer on top of the BiSe surface as a result of the codeposition of Mn and Se. Our experimental results, supported by relativistic ab initio calculations, demonstrate that the fabricated MnBiSe/BiSe heterostructure shows ferromagnetism up to room temperature and a clear Dirac cone gap opening of ∼100 meV without any other significant changes in the rest of the band structure. It can be considered as a result of the direct interaction of the surface Dirac cone and the magnetic layer rather than a magnetic proximity effect. This spontaneously formed self-assembled heterostructure with a massive Dirac spectrum, characterized by a nontrivial Chern number C = -1, has a potential to realize the QAHE at significantly higher temperatures than reported up to now and can serve as a platform for developing future >topotronics> devices.This work has been supported by Grants-In-Aid from Japan Society for the Promotion of Science (Nos. 15H05453, 16K13683, 19340078, and 23244066), the Toray Science Foundation, the Basque Country Government, Departamento de Educacion, Universidades e Investigacion (Grant No. IT-756-13), the Spanish Ministry of Science and Innovation (Grant Nos. FIS2010-19609-C02-01, FIS2013- 48286-C02-02-P, and FIS2013-48286-C02-01-P), the Tomsk State University Academic D.I. Mendeleev Fund Program (Grant No. 8.1.05.2015), and Saint Petersburg State University (project 15.61.202.2015). The ARPES experiments were performed under the UVSOR Proposal Nos. 25-808, 26-531, 27-533, 28-526, and S-15-MS-0034, and the SARPES experiments were performed under the HiSOR Proposal No. 15-A14. The XMCD measurements were performed under the UVSOR proposal number S-16-MS-2017. The LEED measurements were performed under the ISSP Proposal number H17-A250. The SQUID measurements were performed using facilities of the Cryogenic Research Center, the University of Tokyo.Peer Reviewe