Intrinsic cellular chirality regulates left–right symmetry breaking during cardiac looping

Abstract

The vertebrate body plan is overall symmetrical but left–right (LR) asymmetric in the shape and positioning of internal organs. Although several theories have been proposed, the biophysical mechanisms underlying LR asymmetry are still unclear, especially the role of cell chirality, the LR asymmetry at the cellular level, on organ asymmetry. Here with developing chicken embryos, we examine whether intrinsic cell chirality or handedness regulates cardiac C looping. Using a recently established biomaterial-based 3D culture platform, we demonstrate that chick cardiac cells before and during C looping are intrinsically chiral and exhibit dominant clockwise rotation in vitro. We further show that cells in the developing myocardium are chiral as evident by a rightward bias of cell alignment and a rightward polarization of the Golgi complex, correlating with the direction of cardiac tube rotation. In addition, there is an LR polarized distribution of N-cadherin and myosin II in the myocardium before the onset of cardiac looping. More interestingly, the reversal of cell chirality via activation of the protein kinase C signaling pathway reverses the directionality of cardiac looping, accompanied by a reversal in cellular biases on the cardiac tube. Our results suggest that myocardial cell chirality regulates cellular LR symmetry breaking in the heart tube and the resultant directionality of cardiac looping. Our study provides evidence of an intrinsic cellular chiral bias leading to LR symmetry breaking during directional tissue rotation in vertebrate development.

Making and breaking symmetry in development, growth and disease

“…For example, the dextral looping of the zebrafish heart is controlled by a heart-intrinsic cytoskeletondependent mechanism (Desgrange et al, 2018;Noël et al, 2013). Thus, asymmetric information is transferred from smaller to larger scales multiple times independently within the same embryo (Chin et al, 2018;Ray et al, 2018), rather than emerging in a single symmetry-breaking event.…”

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

“…Chick embryonic cardiac cells exhibit intrinsic cell chirality prior to looping, which ensures a dominant clockwise rotation. Like the Drosophila hindgut, these cells exhibit polarized Cadherin and Myosin molecules prior to cardiac looping (Ray et al 2018). Further, it is known that L/R asymmetry in vertebrates is dictated by the floor plate, an analogous embryonic landmark to the Drosophila midline cells.…”

Cells with Broken Left–Right Symmetry: Roles of Intrinsic Cell Chirality in Left–Right Asymmetric Epithelial Morphogenesis

“…Today, links between chirality at the molecular and organismal levels are slowly beginning to be understood [7][8][9][10]. Notably, between these two layers of biological chirality, chirality at the cellular level was discovered [10][11][12][13][14][15][16][17].…”

“…Cell chirality has roles in vertebrate LR asymmetric development in parallel with other known mechanisms, such as nodal flow and LR asymmetric proton influx [56,57]. For example, chick cardiac cells show an intrinsic cell chirality that is responsible for the LR asymmetry break in cardiac looping [17]. In addition, cell chirality may be involved in the concordant organization of tissue, because the coexistence of cells with different enantiomorphic states of cell chirality within a tissue may introduce disharmony into the tissue's organization.…”