TMED2 is Required for Trophoblast Migration, Differentiation, and Proliferation
Bibliographic record
Abstract
Essential cargo receptors, specifically members of the Transmembrane emp24 domain (TMED) protein family, are implicated in numerous cellular morphogenesis. The localization and levels of TMED proteins are tightly controlled to regulate cell survival, migration, and proliferation. TMED proteins have an N‐terminal coiled‐coil region essential for interactions with TMED partners and a Golgi dynamics (GOLD) domain required for heterodimerization and cargo recognition. Although the structure of TMED2 is known, the function of TMED2 in placental development remains poorly understood. Mouse embryos homozygous for a null mutation in the signal sequence of TMED2 died at midgestation from failure to form a placental labyrinth layer. Moreover, ex vivo cultures of pre‐attachment chorion and allantois suggest that cell‐type‐specific transport of fibronectin and VCAM1, by TMED2, is required for chorionic‐allantoic cell communication and for trophoblast differentiation. Thus, we hypothesize that events necessary for labyrinth layer formation such as trophoblast migration and syncytiotrophoblast fusion, require functional TMED2. To test the role of TMED2 in cell migration and survival, we conducted scratch and viability assays in HEK293 cells overexpressing wild‐type and mutant TMED2. We also tested the effects of mutating residues in the GOLD domain of TMED2, E48 and K91, that are predicted to be involved in heterodimerization with TMED10. We found that HEK293 cells overexpressing wild‐type TMED2 displayed reduced cell migration and increased ER stress. Similarly, overexpression of mutant TMED2‐E48Q, resulted in a comparable reduction in cell migration. However, cells overexpressing TMED2‐K91R, showed increased cell migration and viability compared to TMED2 and TMED2‐E48Q cells. To more precisely investigate the absence of a labyrinth layer in TMED2 deficient embryos, we conducted proliferation and fusion studies in two human choriocarcinoma cell lines: JEG‐3 and BeWo. Overexpression of wild type TMED2 in JEG‐3 cells was sufficient for syncytiotrophoblast fusion; however, knockdown of TMED2 in BeWo cells inhibited fusion, supporting a requirement for TMED2 in this process. Moreover, proliferation and metabolic activity assays revealed that knockdown of TMED2 in BeWo cells increased cell proliferation and decreased cell migration. Overall, our data suggest that levels of TMED2 must be tightly regulated for cell proliferation and viability. In addition, we found that the K91 residue of TMED2, which is predicted to help mediate heterodimerization with TMED10 is important for TMED2 function. We propose that the abnormalities displayed by embryos and cells deficient in or overexpressing TMED2 reflect the inadequate transport and localization of fibronectin and likely more unidentified proteins critical for regulating proliferation and migration of trophoblast cells. Support or Funding Information Natural Sciences and Engineering Research Council of Canada
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".