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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.

SUBMITTER: Baker K

PROVIDER: S-EPMC2544555 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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

Baker Kari K Holtzman Nathalia G NG Burdine Rebecca D RD

Proceedings of the National Academy of Sciences of the United States of America 20080910 37

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 ...[more]

PMID: 18784369

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Project description:AimsVertebrate heart development requires the complex morphogenesis of a linear tube to form the mature organ, a process essential for correct cardiac form and function, requiring coordination of embryonic laterality, cardiac growth, and regionalized cellular changes. While previous studies have demonstrated broad requirements for extracellular matrix (ECM) components in cardiac morphogenesis, we hypothesized that ECM regionalization may fine tune cardiac shape during heart development.Methods and resultsUsing live in vivo light sheet imaging of zebrafish embryos, we describe a left-sided expansion of the ECM between the myocardium and endocardium prior to the onset of heart looping and chamber ballooning. Analysis using an ECM sensor revealed the cardiac ECM is further regionalized along the atrioventricular axis. Spatial transcriptomic analysis of gene expression in the heart tube identified candidate genes that may drive ECM expansion. This approach identified regionalized expression of hapln1a, encoding an ECM cross-linking protein. Validation of transcriptomic data by in situ hybridization confirmed regionalized hapln1a expression in the heart, with highest levels of expression in the future atrium and on the left side of the tube, overlapping with the observed ECM expansion. Analysis of CRISPR-Cas9-generated hapln1a mutants revealed a reduction in atrial size and reduced chamber ballooning. Loss-of-function analysis demonstrated that ECM expansion is dependent upon Hapln1a, together supporting a role for Hapln1a in regionalized ECM modulation and cardiac morphogenesis. Analysis of hapln1a expression in zebrafish mutants with randomized or absent embryonic left-right asymmetry revealed that laterality cues position hapln1a-expressing cells asymmetrically in the left side of the heart tube.ConclusionWe identify a regionalized ECM expansion in the heart tube which promotes correct heart development, and propose a novel model whereby embryonic laterality cues orient the axis of ECM asymmetry in the heart, suggesting these two pathways interact to promote robust cardiac morphogenesis.

Dataset Information

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

Publications

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

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