Postnatal heart development is coordinated by multi-lineage Wnt and BMP signaling

Early postnatal heart growth requires a transition from cardiomyocyte proliferation to enlargement and binucleation. Using morphometric, transcriptomic, signaling, and single-cell analyses in neonatal mice, we show that this transition occurs predominantly between postnatal day 3.5 and 4.5 (P3.5–P4.5), accompanied by declining β-catenin abundance and increased SMAD1/5/9 phosphorylation. Pharmacological disruption of β-catenin/CBP signaling or Ctnnb1 knockdown promotes cardiomyocyte enlargement, whereas β-catenin stabilization by CHIR-99021 enhances cell-cycle activity and estimated ventricular cardiomyocyte number while limiting enlargement. Transcriptomic analysis reveals a Sox2/Zic1/Olig2 module enriched in early neural/glial cells, suggesting the onset of postnatal cardiac nervous system development. Wnt pathway components are active in endothelial, mesenchymal, and neural populations during the early postnatal window, whereas BMP signaling peaks in cardiomyocytes at P6. These findings reveal a multi-lineage interplay between Wnt and BMP signaling that balances cardiomyocyte number expansion versus enlargement during early postnatal heart development.