Mesodermal fibronectin controls cell shape, polarity, and mechanotransduction in the second heart field during cardiac outflow tract development

Failure in the elongation of the cardiac outflow tract (OFT) results in congenital heart disease due to the misalignment of the great arteries with the left and right ventricles. The OFT lengthens via the accretion of progenitors from the second heart field (SHF). SHF cells are exquisitely regionalized and organized into an epithelial-like layer, forming the dorsal pericardial wall (DPW). Tissue tension, cell polarity, and proliferation within the DPW are important for the addition of SHF-derived cells to the heart and OFT elongation. However, the genes controlling these processes are not completely characterized. Using conditional mutagenesis in the mouse, we show that fibronectin (FN1) synthesized by the mesoderm coordinates multiple cellular behaviors in the anterior DPW. FN1 is enriched in the anterior DPW and plays a role in OFT elongation by maintaining a balance between pro- and anti-adhesive cell-extracellular matrix (ECM) interactions and controlling DPW cell shape, polarity, cohesion, proliferation, and mechanotransduction. [Display omitted] •FN1 expression is enriched in the anterior dorsal pericardial wall (aDPW)•In the absence of mesodermal FN1, DPW cell-ECM interactions with TNC prevail•FN1-null DPW cells become round, lose epithelial properties, and lose nuclear YAP1•Mesodermal FN1 controls DPW properties and cardiac OFT elongation cell autonomously Elongation of the cardiac outflow tract is essential for the development of the heart’s arterial pole. Arriagada et al. show that FN1 synthesized by the mesoderm controls outflow tract elongation in a cell-autonomous manner by controlling epithelial and mechanical properties of SHF-derived cells in the anterior DPW and counteracting TNC.