Direct and indirect roles for Nodal signaling in two axis conversions during asymmetric morphogenesis of the zebrafish heart

Abstract

The Nodal signaling pathway plays a conserved role in determining left-sided identity in vertebrates with this early left-right (L/R) patterning influencing the asymmetric development and placement of visceral organs. We have studied the role of Nodal signaling in asymmetric cardiac morphogenesis in zebrafish and describe two distinct rotations occurring within the heart. The first is driven by an asymmetric migration of myocardial cells during cardiac jogging, resulting in the conversion of the L/R axis to the dorsal-ventral (D/V) axis of the linear heart. This first rotation is directly influenced by the laterality of asymmetric gene expression. The second rotation occurs before cardiac looping and positions the original left cells exposed to Nodal signaling back to the left of the wild-type (WT) heart by 48 hours postfertilization (hpf). The direction of this second rotation is determined by the laterality of cardiac jogging and is not directly influenced by asymmetric gene expression. Finally, we have identified a role for Nodal signaling in biasing the location of the inner ventricular and outer atrial curvature formations. These results suggest that Nodal signaling directs asymmetric cardiac morphogenesis through establishing and subsequently reinforcing laterality information over the course of cardiac development.asymmetry ͉ southpaw ͉ switch hitter ͉ cardiac ͉ rotation N odal signaling plays a conserved role in creating initial differences between the left and right sides of the vertebrate embryo. Alterations in early, left-specific expression of Nodal and its downstream targets results in abnormal organ placement and morphogenesis later in development (1). In zebrafish, the nodal gene southpaw (spaw) regulates the migration of the posterior lateral plate mesoderm (LPM) at the level of the gut tube and affects asymmetric budding of the liver (2). The nodal target pitx2 has been shown to regulate the specification of the left atrium and asymmetric development of the outflow tract myocardium in the mouse heart (3, 4). However, there is little evidence of a direct function for Nodal signaling in the establishment of initial morphological asymmetries in the anterior LPM.To address this question, we studied asymmetric cardiac development in zebrafish. The zebrafish heart undergoes two distinct asymmetric events. During the first process of cardiac jogging, a disk-shaped structure called the cardiac cone is converted to a linear heart tube by the repositioning of the atrial cells to the anterior and left of the ventricular cells (5, 6). These movements occur concurrently with asymmetric spaw expression in the left LPM. The second asymmetry, cardiac looping, is conserved in all vertebrates and positions the ventricle to the right of the atrium (5). In zebrafish, this process is initiated 10 h after spaw is expressed in the left LPM (7). We have examined both of these events and what role Nodal signaling plays in directing these asymmetries.We find that the laterality of cardiac jogging is determined by a direc...

Retinoic Acid Signaling Sequentially Controls Visceral and Heart Laterality in Zebrafish

“…3). It has been reported that spaw morphant displays disturbed cardiac bmp4 asymmetry as well as defective heart laterality (11,21), and reversed asymmetry of lefty2 is accompanied by reversed heart laterality (50). However, it is likely that if the left-sided Nodal is present, repression of the Nodal signal in the right LPM is less significant for cardiac bmp4 asymmetry and heart laterality (Figs.…”

A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality

“…During heart tube formation, the cardiac disc undergoes an asymmetric tissue rearrangement that includes rotation of the cardiac disc and local invagination at the right side. This reorganization results in the left side of the disc, ultimately forming the dorsal face of the heart tube [19][20][21] . It has been suggested that such rotational events may provide directed torsion in the heart tube, which in turn may drive directional looping 20,[22][23][24][25] .…”

“…Mutant embryos with disrupted cilia-mediated fluid flow in the KV display a wide variety of laterality defects [17][18][19] . To determine whether the residual cardiac-specific directional bias in sfw mutants is the result of alternative signals under the control of KV function, we analysed heart-looping direction in dnaaf1 mutants with immotile cilia 18,19 . Surprisingly, dnaaf1 mutants or sfw/dnaaf1 double-mutant embryos still exhibited a significant preferred dextral heart loop ( Fig.…”

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

“…Nodal, a member of the transforming growth factor-b (TGF-b) family, has essential roles during embryogenesis, such as formation of mesoderm and patterning of left-right axis (Schier and Shen, 2000;Shen, 2007;Baker et al, 2008). Recently, we have shown that Nodal and its receptors, activin receptor-like kinase 7 (ALK7) and ALK4, are expressed in human ovarian cancer cells .…”