Left‐right lineage analysis of the embryonic Xenopus heart reveals a novel framework linking congenital cardiac defects and laterality disease

Abstract

Heterotaxy syndrome is characterized by abnormal thoracic and/or visceral organ left-right (LR) asymmetry. The significant morbidity and mortality associated with heterotaxy almost always are attributed to complex cardiac defects, reflecting the extreme susceptibility of the developing heart to disturbances in the LR body plan. To determine how LR positional information becomes “translated” into cardiac anatomical asymmetry, we used in vivo markers to trace left (L) vs. right (R) side cardiomyocyte lineages in embryos of the frog, Xenopus laevis. In controls, we find that some regions of the heart are derived from a unilateral lineage, whereas other regions are derived from both L and R lineages. However, in embryos with situs defects experimentally induced by misregulated ALK4 signaling, hearts of heterotaxic embryos show abnormal cell lineage compositions that usually correspond with abnormal cardiac anatomy. Furthermore, hearts of embryos exhibiting situs inversus show a mirror image reversal in cell contributions in addition to the complete inversion of organ asymmetry that is characteristic of this condition. Together, these results demonstrate that i) different regions of the heart contain distinct LR cell compositions; ii) LR myocyte compositions are altered in embryos with laterality defects; and iii) abnormal LR lineage allocation is associated with cardiac defects. We propose that distinct LR cell compositions in different regions of the heart are necessary for normal morphogenesis, and that abnormal LR cell lineage compositions are causatively linked with specific types of cardiac defects.