The dynamic roles of Tbx5 in murine cardiac development: A spatiotemporal and dosage-dependent analysis
Bibliographic record
Abstract
Dominant mutations in the T-box transcription factor TBX5 cause Holt Oram syndrome (HOS), an inherited human disease characterized by upper limb malformations and congenital heart defects (CHDs) of variable severity. While occurrences of HOS are rare, the spectrum of CHDs related to TBX5 haploinsufficiency (septal and conduction defects) occur frequently within the general population. Moreover, the discovery of human somatic mutations of TBX5 in non-HOS syndrome patients presenting with CHDs underscores the importance of developing a detailed understanding of the roles of TBX5 during cardiogenesis. Using a temporally-inducible Cre, I proceed to show that Tbx5 acts initially to specify gross atrio-ventricular patterning, and later to refine boundary elements between cardiac chambers. This shows an uncoupling of early differentiation from later fine morphogenesis of distinct cardiac structures and supports a role for Tbx5 in directly patterning specific structures during later cardiogenesis. Using a previously generated Tbx5 conditional mouse mutant, I have dissected the dosage-dependent requirements for, and the spatiotemporal roles of Tbx5 during early cardiogenesis. Analysis of a Tbx5 allelic series shows an inverse correlation between Tbx5 dosage and abnormal cardiac morphogenesis, which is likely underpinned by differential sensitivities of downstream genes to varying levels of Tbx5. These differences in dosage, due to slightly different genetic backgrounds, likely account for the variation in severity of HOS clinical presentation. These initial studies identified a critical requirement for Tbx5 in the outgrowth of the interventricular septum (IVS) between E9-10, which was investigated using two different ventricle-restricted Cre lines. I demonstrate that Tbx5 is necessary to specify ventricular chamber identity and is required explicitly at the interventricular midpoint for IVS outgrowth and the development of the distal conduction system. The defects caused by the ventricular disruption of Tbx5 expression further underscores the pleiotropic nature of this transcription factor in establishing chamber boundary element identity and shows a direct role for Tbx5 in positioning and outgrowth of the IVS. The studies presented here extend the understanding of the role of Tbx5 in cardiogenesis, arguing that CHD manifestation is influenced both globally by dosage considerations, and locally through spatiotemporal changes within chamber precursors.
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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 | 0.001 | 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) | 0.001 | 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 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".