A right-handed signalling pathway drives heart looping in vertebrates

Abstract

The majority of animals show external bilateral symmetry, precluding the observation of multiple internal left-right (L/R) asymmetries that are fundamental for organ packaging and function1,2. In vertebrates, left identity is mediated by the left-specific Nodal-Pitx2 axis that is repressed on the right-hand side by the epithelial-mesenchymal transition (EMT) inducer Snail13,4. Despite some existing evidence3,5, it remains unclear whether an equivalent instructive pathway provides right-hand specific information to the embryo. Here we show that in zebrafish, BMP mediates the L/R asymmetric activation of another EMT inducer, Prrx1a, in the lateral plate mesoderm (LPM) with higher levels on the right. Prrx1a drives L/R differential cell movements towards the midline leading to a leftward displacement of the cardiac posterior pole through an actomyosin-dependent mechanism. Downregulation of Prrx1a prevents heart looping and leads to mesocardia. Two parallel and mutually repressed pathways, respectively driven by Nodal and BMP on the left and right LPM, converge on the asymmetric activation of Pitx2 and Prrx1, two transcription factors that integrate left and right information to govern heart morphogenesis. This mechanism is conserved in the chicken embryo and, in the mouse, Snail1 fulfills the role played by Prrx1 in fish and chick. Thus, a differential L/R EMT produces asymmetric cell movements and forces, more prominent from the right, that drive heart laterality in vertebrates.

Development and evolution of the metazoan heart

“…During embryonic development, hearts of all vertebrates exhibit a kind of looping, which is governed by a righthanded signaling pathway involving Nodal, BMP, and Pitx2. 107 In fish, addition of SHF-derived cells 47 results in a limited elongation of the primitive heart tube, probably accompanied by a restricted repositioning of atrium and ventricle. In other vertebrates, the elongation process continues, probably by more massive addition of SHF cells to the FHFderived primitive heart tube.…”

Skin regeneration of amphibians: A novel model for skin regeneration as adults

“…If a full-thickness skin flap is excised at the dor- Similarly, muscles are fragmenting in and around the original wound after excisional skin removal in adult axolotls (Seifert, Monaghan, et al, 2012). Limb blastema cells specifically express a paired-type homeobox-containing transcription factor, prx1 (also called prrx1, e.g., Norris et al, 2000;Ocaña et al, 2017), in limb regeneration of amphibians (Satoh, Gardiner, Bryant & Endo, 2007;Suzuki et al, 2005). As a result of "dedifferentiation," blastema cells accumulate under the epidermis in limb regeneration of amphibians (Han et al, 2005;Straube & Tanaka, 2006;Suzuki et al, 2006).…”

“…As a result of "dedifferentiation," blastema cells accumulate under the epidermis in limb regeneration of amphibians (Han et al, 2005;Straube & Tanaka, 2006;Suzuki et al, 2006). Limb blastema cells specifically express a paired-type homeobox-containing transcription factor, prx1 (also called prrx1, e.g., Norris et al, 2000;Ocaña et al, 2017), in limb regeneration of amphibians (Satoh, Gardiner, Bryant & Endo, 2007;Suzuki et al, 2005). In skin regeneration of a Xenopus laevis froglet, cells that accumulate under the wound epidermis express the limb blastema marker prx1 on the limb and trunk after excisional skin re- Therefore, blastema-like cells, which are marked by activation of the prx1 limb-specific enhancer, accumulate under the wound epidermis in the trunk as well as the limb region in the skin regeneration process of a Xenopus laevis froglet.…”

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

“…According to previous studies, Foxh1 is expressed throughout the mouse embryo as the gastrulation stage; then, its expression is restricted to the heart‐forming regions from E8.0 to E9.5 . Prior studies have shown that Foxh1 governs heart morphogenesis, particularly the development of the right ventricle (RV) and OFT, via direct regulation of the transcription of Pitx2 and Mef2c , which interact with Nkx2.5 and Smads . For example, Foxh1 −/− mouse embryos exhibit abnormalities in the OFT and RV despite normal development of a primitive heart tube .…”

“…14,15 Prior studies have shown that Foxh1 governs heart morphogenesis, particularly the development of the right ventricle (RV) and OFT, via direct regulation of the transcription of Pitx2 and Mef2c, which interact with Nkx2.5 and Smads. [16][17][18] For example, Foxh1 −/− mouse embryos exhibit abnormalities in the OFT and RV despite normal development of a primitive heart tube. 16 In short, FOXH1 plays a significant role in the cardiogenic lineage development of the AHF and mediates the formation of RV and OFT during heart looping morphogenesis.…”