title: Left-right lineage analysis of the embryonic Xenopus heart reveals a novel framework linking congenital cardiac defects and laterality disease.
abstract: The significant morbidity and mortality associated with laterality disease almost always are attributed to complex congenital heart defects (CHDs), reflecting the extreme susceptibility of the developing heart to disturbances in the left-right (LR) body plan. To determine how LR positional information becomes ;translated' into anatomical asymmetry, left versus right side cardiomyocyte cell lineages were traced in normal and laterality defective embryos of the frog, Xenopus laevis. In normal embryos, myocytes in some regions of the heart were derived consistently from a unilateral lineage, whereas other regions were derived consistently from both left and right side lineages. However, in heterotaxic embryos experimentally induced by ectopic activation or attenuation of ALK4 signaling, hearts contained variable LR cell composition, not only compared with controls but also compared with hearts from other heterotaxic embryos. In most cases, LR cell lineage defects were associated with abnormal cardiac morphology and were preceded by abnormal Pitx2c expression in the lateral plate mesoderm. In situs inversus embryos there was a mirror image reversal in Pitx2c expression and LR lineage composition. Surprisingly, most of the embryos that failed to develop heterotaxy or situs inversus in response to misregulated ALK4 signaling nevertheless had altered Pitx2c expression, abnormal cardiomyocyte LR lineage composition and abnormal heart structure, demonstrating that cardiac laterality defects can occur even in instances of otherwise normal body situs. These results indicate that: (1) different regions of the heart contain distinct LR myocyte compositions; (2) LR cardiomyocyte lineages and Pitx2c expression are altered in laterality defective embryos; and (3) abnormal LR cardiac lineage composition frequently is associated with cardiac malformations. We propose that proper LR cell composition is necessary for normal morphogenesis, and that misallocated LR cell lineages may be causatively linked with CHDs that are present in heterotaxic individuals, as well as some 'isolated' CHDs that are found in individuals lacking overt features of laterality disease.
authors.affiliation: Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, 29208, USA. ramsdell@musc.edu
authors.forename: Ann F
authors.initials: AF
authors.lastname: Ramsdell
authors.forename: Jayne M
authors.initials: JM
authors.lastname: Bernanke
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Trusk
mesh_terms: D029404:Activin Receptors / Q000235:genetics / Q000378:metabolism; D030201:Activin Receptors, Type I; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D019070:Cell Lineage; D004625:Embryo, Nonmammalian; D005318:Fetal Heart / Q000196:embryology* / Q000378:metabolism; D007839:Functional Laterality; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D018613:Microscopy, Confocal; D012857:Situs Inversus / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D014981:Xenopus / Q000196:embryology*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C438620:Pitx2c protein, Xenopus; D029867:Xenopus Proteins; D029404:Activin Receptors; D030201:Activin Receptors, Type I; C481805:acvr1b protein, Xenopus