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Background  Left-right (LR) asymmetry is an essential feature of bilateral animals. Studies in vertebrates show that LR asymmetry formation comprises three major steps: symmetry breaking, asymmetric gene expression, and LR morphogenesis. Although much progress has been made in the first two events, mechanisms underlying asymmetric morphogenesis remain largely unknown due to the complex developmental processes deployed by vertebrate organs.    Results  We here addressed this question by studying  Pitx  gene function in the basal chordate amphioxus whose asymmetric organogenesis, unlike that in vertebrates, occurs essentially in situ and does not rely on cell migration.  Pitx  null mutation in amphioxus causes loss of all left-sided organs and incomplete ectopic formation of all right-sided organs on the left side, whereas  Pitx  partial loss-of-function leads to milder phenotypes with only some LR organs lost or ectopically formed. At the N1 to N3 stages,  Pitx  expression is gradually expanded from the dorsal anterior domain to surrounding regions. This leads to activation of genes like  Lhx3  and/or  Prop1  and  Pit , which are essential for left-side organs, and downregulation of genes like  Hex  and/or  Nkx2.1  and  FoxE4 , which are required for right-side organs to form ectopically on the left side. In  Pitx  mutants, the left-side expressed genes are not activated, while the right-side genes fail to decrease expression on the left side. In contrast, in embryos overexpressing  Pitx  genes, the left-side genes are induced ectopically on the right side, and the right-side genes are inhibited. Several  Pitx  binding sites are identified in the upstream sequences of the left-side and right-side genes which are essential for activation of the former and repression of the latter by  Pitx .    Conclusions  Our results demonstrate that (1)  Pitx  is a major (although not the only) determinant of asymmetric morphogenesis in amphioxus, (2) the development of different LR organs have distinct requirements for  Pitx  activity, and (3)  Pitx  controls amphioxus LR morphogenesis probably through inducing left-side organs and inhibiting right-side organs directly. These findings show much more dependence of LR organogenesis on  Pitx  in amphioxus than in vertebrates. They also provide insight into the molecular developmental mechanism of some vertebrate LR organs like the lungs and atria, since they show a right-isomerism phenotype in  Pitx2  knockout mice like right-sided organs in  Pitx  mutant amphioxus. Our results also explain why some organs like the adenohypophysis are asymmetrically located in amphioxus but symmetrically positioned in vertebrates.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12915-021-01095-0.

Pitx controls amphioxus asymmetric morphogenesis by promoting left-side development and repressing right-side formation