Abstract
Failure to properly establish the left–right (L/R) axis is a major cause of congenital heart defects in humans, but how L/R patterning of the embryo leads to asymmetric cardiac morphogenesis is still unclear. We find that asymmetric Nodal signaling on the left and Bmp signaling act in parallel to establish zebrafish cardiac laterality by modulating cell migration velocities across the L/R axis. Moreover, we demonstrate that Nodal plays the crucial role in generating asymmetry in the heart and that Bmp signaling via Bmp4 is dispensable in the presence of asymmetric Nodal signaling. In addition, we identify a previously unappreciated role for the Nodal-transcription factor FoxH1 in mediating cell responsiveness to Bmp, further linking the control of these two pathways in the heart. The interplay between these TGFβ pathways is complex, with Nodal signaling potentially acting to limit the response to Bmp pathway activation and the dosage of Bmp signals being critical to limit migration rates. These findings have implications for understanding the complex genetic interactions that lead to congenital heart disease in humans.
Highlights
Establishment of asymmetries along the left–right (L/R) axis is critically important for proper placement, morphogenesis and functioning of vertebrate organs [1,2]
The Nodal and Bmp signaling pathways influence the development of cardiac asymmetry, but how these signals function in this process is not well understood
We find that Nodal signals increase the rate of cardiac cell migration, while Bmp signals decrease cardiac cell velocities
Summary
Establishment of asymmetries along the left–right (L/R) axis is critically important for proper placement, morphogenesis and functioning of vertebrate organs [1,2]. While the laterality of Nodal signaling has been shown to influence the direction of cardiac cell migration [9], the Bmp pathway has been implicated as providing the dominant laterality cue to the heart [12]. We find that the Nodal signaling pathway provides the dominant laterality cue to the heart and directs cardiac cell migration by increasing cell velocities on the left of the wild type (WT) cardiac cone. Our results are consistent with a role for BMP signaling in limiting cell migration on the right side of the cardiac cone, while the Bmp pathway has historically been thought to positively regulate cell migration and act predominantly on the left of the developing heart [12,13,14]. In the absence of Nodal signaling, the heart is extremely
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