Epithelial tension in the second heart field promotes mouse heart tube elongation

Abstract

Extension of the vertebrate heart tube is driven by progressive addition of second heart field (SHF) progenitor cells to the poles of the heart. Defects in this process cause a spectrum of congenital anomalies. SHF cells form an epithelial layer in splanchnic mesoderm in the dorsal wall of the pericardial cavity. Here we report oriented cell elongation, polarized actomyosin distribution and nuclear YAP/TAZ in a proliferative centre in the posterior dorsal pericardial wall during heart tube extension. These parameters are indicative of mechanical stress, further supported by analysis of cell shape changes in wound assays. Time course and mutant analysis identifies SHF deployment as a source of epithelial tension. Moreover, cell division and oriented growth in the dorsal pericardial wall align with the axis of cell elongation, suggesting that epithelial tension in turn contributes to heart tube extension. Our results implicate tissue-level forces in the regulation of heart tube extension.

Tbx1regulates extracellular matrix-cell interactions in the second heart field

“…3C-D). The altered distribution of NMIIB reinforces the idea that TBX1 supports the ability of the eSHF to undergo morphogenetic changes, acquiring epithelial features which are essential for proper heart morphogenesis (13,14).…”

“…The localization of most of these proteins and the polarity of eSHF cells is severely altered in mutant embryos, thus compromising the cohesiveness of the epithelial cell layer and providing a mechanistical basis for the previously observed cell roundness and protrusion phenotype (13). In addition, these polarity and cohesiveness defects could also explain the loss of tension within the SHF (14) and the reduced contribution of SHF cells to the heart in these mutants. Our results thus reinforce and extend the emerging paradigm that regulation of the epithelial properties of cardiac progenitor cells in the SHF is a critical step in early heart morphogenesis.…”

“…At the apical/lateral region of the eSHF we also found a contractile protein, NMIIB/MYH10, a non-muscle myosin that maintains cortical tension and cell shape, and is required for heart development (19,21,43,44), although its specific role in the SHF has not been determined. The consequences of NMIIB mislocalization caused by loss of TBX1 are still unclear, but recent data has shown that disruption of the actomyosin machinery using a ROCK inhibitor changes cells shape but does not seem to affect epithelial tension in the SHF, consistent with a role for actomyosin in preventing cell distortion in the SHF in response to epithelial tension rather than regulating tension itself (14).…”

“…The epithelial properties of the SHF are emerging as a critical regulatory step during the process of heart tube elongation, yet how regulators of SHF deployment impact on SHF cell biology remains poorly understood (10). Tbx1 has been shown to be required for progenitor recruitment to the heart (11,12) and its loss has been associated with disruption of epithelial polarity in the DPW (13), and reduced tension of the epithelial sheet (14), although the mechanisms by which these phenotypic anomalies occur remain unclear. Planar cell polarity (PCP) genes Dvl2 and Wnt5a have been proposed to be part of this process by facilitating the incorporation, by intercalation, of mesenchymal cells into the epithelial sheet of the DPW (15)(16)(17).…”

Continuous addition of progenitors forms the cardiac ventricle in zebrafish

“…After the early-differentiating FHF assembles the linear heart tube that in mammals forms the left ventricle and parts of the atria, the late-differentiating SHF contributes to the atria, right ventricle, and OFT (Kelly, 2012;Kelly et al, 2001;Mjaatvedt et al, 2001;Tzahor and Evans, 2011). In mice, the SHF forms within medial and posterior epithelial-like field in the splanchnic ALPM on either side of the FHF-derived cardiac crescent and is detectable through expression of markers including Fgf10 and Isl1 (Cai et al, 2003;Francou et al, 2017;Kelly et al, 2001). Developmental defects in SHF contribution to the heart lead to a broad variety of congenital heart defects affecting the arterial pole (Srivastava and Olson, 2000).…”