Dynamin 2‐Dependent Endocytosis is Required For Normal Megakaryocyte Development
Bibliographic record
Abstract
Dynamins are large and highly conserved GTPases involved in a wide range of cellular functions, including endocytosis and vesicle trafficking, and mutations in the ubiquitous dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in megakaryopoiesis we generated Dnm2fl/fl Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2fl/fl Pf4-Cre mice had severe macrothrombocytopenia with moderately accelerated platelet clearance. Dnm2-null bone marrow MKs had altered DMS, appearing at times as a compact, narrow twisting membrane system of clathrin-coated vesicles. The endocytic pathway was disrupted in Dnm2-null MKs, as evidenced by reduced early endosome EEA1 and APPL1 staining. MK-specific DNM2 deletion severely disrupted bone marrow homeostasis, as indicated by massive MK hyperplasia, myelofibrosis, and consequent extramedullary hematopoiesis and splenomegaly. Endocytosis of the thrombopoietin (TPO) receptor Mpl was impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating TPO levels. However, additional Mpl genetic deletion failed to rescue the severe splenomegaly of Dnm2fl/fl Pf4-Cre mice, and Mpl-/- Dnm2fl/fl Pf4-Cre mice died at 4-5 weeks of age. Taken together, our data establishes a previously unrecognized role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis and bone marrow homeostasis.
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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 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".