Vinculin mediates a dynamic signal flow underlying cardiac outflow tract development as revealed by single-cell and spatial transcriptomic analysis
Bibliographic record
Abstract
INTRODUCTION: Cardiac outflow tract (OFT) development relies on the interactions among cardiac neural crest cells (CNCC) and the second heart field (SHF) cells. However, the molecular signals underlying these interactions remain largely unclear. OBJECTIVES: Vinculin (VCL) is an adaptor protein for focal adhesions, which integrates various external signals and mediates cell-cell communications, representing a potential hub gene directing the OFT development. Here, we aimed to build a holistic map of signal flows underlying CNCC-directed OFT development using neural crest-specific Vcl knockout mouse mutants (Vcl cKO). METHODS: We validated the OFT defects of Vcl cKO mutants by performing various immunohistochemistry analyses. Subsequent high-resolution transcriptomic analysis reconstructed the differentiation trajectory of CNCCs along the vascular smooth muscle (VSMC) lineage. The spatial RNA-seq further aligned the transcriptomes of OFT cells with their spatial patterns to explore the cell interaction dynamics among OFT cells. Exploiting human pluripotent stem cell (hPSC)-based in vitro differentiation assays, the signaling pathways underlying Vcl-mediated CNCC progression along the VSMC lineage were defined. RESULTS: Vcl cKO exhibited malformation of pharyngeal arch arteries, OFT septation defects and hyperplastic semilunar valves, due to defects in migration and vascular smooth muscle (VSMC) lineage differentiation of CNCCs, which prohibited the subsequent myocardialization, perturbing the OFT and valve remodeling. High-resolution transcriptomic analysis revealed that CNCC-to-VSMC differentiation is orchestrated by Vcl-dependent p38 and Tgf-β signalings. Multimodal analysis integrating the single-cell and spatial transcriptomes of OFT cells further suggested a shift of signal flow among OFT cells and loss of cell-extracellular matrix interaction perturb OFT morphogenesis. CONCLUSION: In sum, dynamic signal flows among CNCC and SHF cells guide OFT remodeling, in which p38-Tgf-β signaling mediates the VSMC lineage differentiation of CNCCs, and timely regulates their interactions with SHF-derived cells through ECM.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".