Mechanisms of left–right symmetry breaking across scales

Abstract

Establishment of left–right (LR) asymmetry relies on a multistep interplay of molecular signaling and physical processes. Initial LR symmetry breaking in several model vertebrates was shown to take place at the LR organizer (LRO) where chiral rotation of monocilia produces a leftward fluid flow. Subsequent bending of sensory cilia triggers Pkd2-channel–mediated calcium transients which in turn are required for induction of asymmetrical signaling upstream of morphological asymmetries, emphasizing the role of mechanosensation in flow detection. Crucially, unidirectional flow and its detection were suggested to require cellular-scale asymmetries including planar cell polarity–mediated posterior position and ultrastructural chirality of motile cilia as well as asymmetric Pkd2 localization within sensory cilia. Alternative mechanisms of LR symmetry breaking operate in models like the chick embryo, where asymmetry of gene expression is preceded by leftward primitive node rotation suggesting mechanisms based on cytoskeletal chirality known from invertebrate models including Caenorhabditis elegans and fruit fly. Investigation of chirality at the cellular level suggests that chirality of components of cytoskeleton, particularly actin filaments, is amplified by distinct modules based i.e. on formin-actin and myosin-actin interactions which drive intracellular swirling and cortical flow, providing a basis for LR asymmetry. Cellular chirality can organize LR asymmetry of multicellular behavior as observed in the chiral alignment of fibroblasts. The integration of molecular, cellular, and tissue-scale chirality highlights conserved and divergent mechanisms underpinning LR symmetry breaking across species. Unraveling these processes may illuminate pathways connecting cytoskeletal dynamics to organismal asymmetry, offering insights into development and evolution.