Membrane translocation of t-SNARE protein syntaxin-4 abrogates ground-state pluripotency in mouse embryonic stem cells
| Autor: | Kota Shirai, Akihiro Yasue, Tomoatsu Horigome, Natsumi Hagiwara-Chatani, Naoki Adachi, Yohei Hirai, Takumi Kido |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Homeobox protein NANOG Rex1 Cellular differentiation MAP Kinase Kinase 2 MAP Kinase Kinase 1 Cell morphology Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine Animals Stem Cell Niche Protein kinase A Induced pluripotent stem cell Protein kinase B Protein Kinase Inhibitors Embryonic Stem Cells Multidisciplinary Glycogen Synthase Kinase 3 beta Chemistry Qa-SNARE Proteins Cell Membrane Cell Differentiation Cadherins Embryonic stem cell Cell biology Culture Media 030104 developmental biology 030220 oncology & carcinogenesis Transcriptome Proto-Oncogene Proteins c-akt |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Embryonic stem (ES) and induced pluripotent stem (iPS) cells are attractive tools for regenerative medicine therapies. However, aberrant cell populations that display flattened morphology and lose ground-state pluripotency often appear spontaneously, unless glycogen synthase kinase 3β (GSK3β) and mitogen-activated protein kinase kinase (MEK1/2) are inactivated. Here, we show that membrane translocation of the t-SNARE protein syntaxin-4 possibly is involved in this phenomenon. We found that mouse ES cells cultured without GSK3β/MEK1/2 inhibitors (2i) spontaneously extrude syntaxin-4 at the cell surface and that artificial expression of cell surface syntaxin-4 induces appreciable morphological changes and mesodermal differentiation through dephosphorylation of Akt. Transcriptome analyses revealed several candidate elements responsible for this, specifically, an E-to P-cadherin switch and a marked downregulation of Zscan4 proteins, which are DNA-binding proteins essential for ES cell pluripotency. Embryonic carcinoma cell lines F9 and P19CL6, which maintain undifferentiated states independently of Zscan4 proteins, exhibited similar cellular behaviors upon stimulation with cell surface syntaxin-4. The functional ablation of E-cadherin and overexpression of P-cadherin reproduced syntaxin-4-induced cell morphology, demonstrating that the E- to P-cadherin switch executes morphological signals from cell surface syntaxin-4. Thus, spontaneous membrane translocation of syntaxin-4 emerged as a critical element for maintenance of the stem-cell niche. |
| Databáze: | OpenAIRE |
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