A right-handed signalling pathway drives heart looping in vertebrates
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Most animals show external bilateral symmetry, which hinders the observation of multiple internal left-right (L/R) asymmetries that are fundamental to organ packaging and function. 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 Snail1 (refs 3, 4). Despite some existing evidence, 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 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 lateral plate mesoderm, converge on the asymmetric activation of the transcription factors Pitx2 and Prrx1, which integrate left and right information to govern heart morphogenesis. This mechanism is conserved in the chicken embryo, and in the mouse SNAIL1 acts in a similar manner to Prrx1a in zebrafish and PRRX1 in the chick. Thus, a differential L/R EMT produces asymmetric cell movements and forces, more prominent from the right, that drive heart laterality in vertebrates.
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PRRX1 is involved in embryonic development and impacts heart looping and laterality in animal models.
“It is involved in embryonic development, where it was shown to impact heart looping and laterality in animal models18.”
From Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation (2024) · cites this paper as [18]
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Self-citationA patterned human heart tube organoid model generated by pluripotent stem cell self-assemblyPreprint
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Sequential action of JNK genes establishes the embryonic left-right axis
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Proprotein convertase furina is required for heart development in zebrafish
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Additional file 1 of Zebrafish nampt-a mutants are viable despite perturbed primitive hematopoiesis
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- Authors
- Ocaña, O. H., Coskun, H., Minguillón, C., Murawala, P., Tanaka, E. M., Galcerán, J., Muñoz-Chápuli, R., & Nieto, M. A.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Center for Regenerative Therapies Dresden (DE)
- Corresponding author
- Nieto, M. Angela
- ORCID
- Venue
- Nature
- Published
- 2017-09-07
- Volume
- 549
- Issue
- 7670
- Pages
- 86-90
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5590727
- OpenAlex
- W2750910159
- Cited by
- 102
- References
- 57
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 15 · 2021: 14 · 2020: 12 · 2019: 17 · 2018: 19 · 2017: 8
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Universitat Pompeu Fabra
- Ministerio de Economía y Competitividad (SEV- 2013-0317, BFU2014, BFU2014-52299, BFU2008-01042)
- Generalitat Valenciana (PROMETEOII/2013/002)
- Junta de Andalucía (P11-CTS-07564)
- Instituto de Salud Carlos III (RD12/0019‐0022)
- European Regional Development Fund
- FP7 Ideas: European Research Council (322694)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Cognitive Neuroscience › Hemispheric Asymmetry in Neuroscience
- Keywords
- heart looping, left-right asymmetry, BMP signaling, Nodal signaling, SNAI1, epithelial-mesenchymal transition, lateral plate mesoderm, cardiac morphogenesis, mesocardia, PITX2, zebrafish, chick embryo, mouse embryo, organogenesis
- MeSH terms
- Snail Family Transcription Factors, Actomyosin, Animals, Cell Movement, Chick Embryo, Female, Heart, Mesoderm, Morphogenesis, Myocardium, Transcription Factors, Zebrafish, Signal Transduction, Homeodomain Proteins, Zebrafish Proteins, Mice, Epithelial-Mesenchymal Transition
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