Molecular and Developmental Asymmetries of Vertebrate Anterior Somites

Abstract

Bilateral symmetry is a conserved characteristic of most animal body plans. In vertebrates, it is especially apparent in the musculoskeletal system and its embryonic precursor, the somites, in contrast to the asymmetric visceral organs. Traditionally, research on left-right (LR) asymmetry has focused on initial symmetry breaking events at the embryonic organizer and on the transfer and amplification of LR determining signaling cascades in the lateral plate mesoderm (LPM). By contrast, the paraxial mesoderm, including the somites, has been largely overlooked, as somite bilateral symmetry has been assumed to be the default state. Although recent studies suggest that somitogenesis occurs in the context of multiple sources of asymmetry, whether somites are truly symmetric, and to what extent, have remained unclear. To address this question, I characterized morphological and gene expression asymmetries in the early chick embryo. Left somites were larger and more anteriorly positioned than right somites, and gene expression underlying somitogenesis showed corresponding asymmetries. Experiments examining segmentation clock gene oscillation using the chick embryo and in vitro human cell model identified LR patterning signals, particularly NODAL, as a cause of this asymmetry. In addition, gene expression analyses and single-cell RNA sequencing uncovered a previously unrecognized molecular asymmetry of somites. The lateral parts of anterior somites express NODAL and an array of novel LR asymmetric genes. Leveraging this discovery, I examined developmental asymmetry of the anterior somites using GFP somite grafting and electroporation. These approaches revealed a striking contribution of somites to the heart and showed that somite molecular laterality is important for proper cardiac development. Together, these findings provide a comprehensive characterization of morphological, molecular, and developmental asymmetries of somites, demonstrate robust directional asymmetry in the paraxial mesoderm, and expand the scope of LR asymmetry research beyond its traditional focus of tissues and genes.