Prrx1 factor controls organ positioning in vertebrates

Resumen

The majority of animals exhibit an external bilateral symmetry. However, there are numerous internal left–right (L/R) asymmetries, including the morphology and position of several organs. During development, all these asymmetries are established by complex genetic and epigenetic cascades. In vertebrates, left identity is mediated by the TGFβ family member Nodal and its downstream target Pitx2, being both transiently expressed in the left lateral plate mesoderm (LPM). This left-handed information is repressed on the right-hand side by the epithelial-mesenchymal transition (EMT) inducer Snail1. So far, it has been unclear whether an equivalent right-handed pathway is providing instructive information to the right LPM. Recently in our lab, we have identified a right-handed pathway that drives heart looping in zebrafish. This novel pathway is regulated by a BMP-mediated asymmetric L/R activation of Prrx1a, another EMT inducer, in the LPM. Prrx1a is transiently expressed at higher levels on the right-hand side of the embryo, and its downregulation prevents heart looping and leads to mesocardia. Prrx1a drives differential cell movements leading to a leftward displacement of the cardiac posterior pole that promotes dextral looping through an actomyosin-dependent mechanism. Thus, two parallel and mutually repressed pathways exist in the left and right LPM. Activation of Nodal (on the left) and BMP (on the right) converge on the asymmetric activation of two paired-like homeodomain transcription factors, Pitx2 and Prrx1, respectively. As the left cascade has been involved in heart morphogenesis, the integration of both pathways would ultimately govern heart morphogenesis and laterality. In this thesis project, we expanded our study to understand whether this L/R asymmetric signalling pathway is conserved during evolution. Indeed, transient asymmetric distribution of Prrx1 is also evident in the chick LPM, with higher levels on the right-hand side, and downregulation of Prrx1 in the chick embryo also induces mesocardia. The asymmetric L/R Prrx1 expression in the chick is also compatible with the formation of an actomyosin- dependent mechanism. As in the fish, Prrx1 silencing caused a loss of actin fibers and of L/R morphological asymmetry. We find that this mechanism is also conserved in the mouse, where Snail1 fulfils the role of Prrx1 in the fish and chick. Furthermore, we next analysed whether Prrx1 was also important for asymmetric positioning of other organs. Here we show that downregulation of Prrx1a also affects gut looping and impairs the asymmetric positioning of gut, liver and pancreas in zebrafish, leading to embryos in which both the heart and the endodermal organs are kept in the midline. Thus, we propose that a right-handed differential L/R EMT produces asymmetric forces and drives organ laterality in vertebrates.