The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
A right-handed signalling pathway drives heart looping in vertebrates
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A series of normal stages in the development of the chick embryo
Hamburger, V., & Hamilton, H. L. (1951) · Journal of Morphology · doi:10.1002/jmor.1050880104 · Cited by 12,254
Stages of embryonic development of the zebrafish
Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B., & Schilling, T. F. (1995) · Developmental Dynamics · doi:10.1002/aja.1002030302 · Cited by 12,037
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
Nieto, M. A., Huang, R. Y.-J., Jackson, R. A., & Thiery, J. P. (2016) · Cell · doi:10.1016/j.cell.2016.06.028 · Cited by 4,492
Self-citationEfficient genome editing in zebrafish using a CRISPR-Cas system
Hwang, W. Y., Fu, Y., Reyon, D., Maeder, M. L., Tsai, S. Q., Sander, J. D., Peterson, R. T., Yeh, J.-R. J., & Joung, J. K. (2013) · Nature Biotechnology · doi:10.1038/nbt.2501 · Cited by 2,937
Lifeact: a versatile marker to visualize F-actin
Riedl, J., Crevenna, A. H., Kessenbrock, K., Yu, J. H., Neukirchen, D., Bista, M., Bradke, F., Jenne, D., Holak, T. A., Werb, Z., et al. (2008) · Nature Methods · doi:10.1038/nmeth.1220 · Cited by 2,189
Acloque, H., Adams, M. S., Fishwick, K., Bronner-Fraser, M., & Nieto, M. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38019 · Cited by 1,350
Self-citationLee, E.-C., Yu, D., de Velasco, J. M., Tessarollo, L., Swing, D. A., Court, D. L., Jenkins, N. A., & Copeland, N. G. (2001) · Genomics · doi:10.1006/geno.2000.6451 · Cited by 1,180
Ocaña, O. H., Córcoles, R. C., Fabra, À., Moreno‐Bueno, G., Acloque, H., Vega, S., Barrallo‐Gimeno, A., Cano, A., & Nieto, M. A. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.10.012 · Cited by 973
Self-citationGagnon, J. A., Valen, E., Thyme, S. B., Huang, P., Ahkmetova, L., Pauli, A., Montague, T. G., Zimmerman, S., Richter, C., & Schier, A. F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098186 · Cited by 893
Ruzankina, Y., Pinzon‐Guzman, C., Asare, A., Ong, T., Pontano, L. L., Cotsarelis, G., Zediak, V. P., Velez, M., Bhandoola, A., & Brown, E. J. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.03.002 · Cited by 803
Adhesion Functions in Cell Sorting by Mechanically Coupling the Cortices of Adhering Cells
Maître, J., Berthoumieux, H., Krens, G., Salbreux, G., Jülicher, F., Paluch, E. K., & Heisenberg, C. (2012) · Science · doi:10.1126/science.1225399 · Cited by 624
The Mouse Snail Gene Encodes a Key Regulator of the Epithelial-Mesenchymal Transition
Carver, E. A., Jiang, R., Lan, Y., Oram, K. F., & Gridley, T. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.23.8184-8188.2001 · Cited by 624
Improved method for chick whole-embryo culture using a filter paper carrier
Chapman, S. C., Collignon, J., Schoenwolf, G. C., & Lumsden, A. (2001) · Developmental Dynamics · doi:10.1002/1097-0177(20010301)220:3 · Cited by 482
Forces Driving Epithelial Spreading in Zebrafish Gastrulation
Behrndt, M., Salbreux, G., Campinho, P., Hauschild, R., Oswald, F., Roensch, J., Grill, S. W., & Heisenberg, C. (2012) · Science · doi:10.1126/science.1224143 · Cited by 421
Chapter 11 In Situ Hybridization Analysis of Chick Embryos in Whole Mount and Tissue Sections
Nieto, M. A., Patel, K. J., & Wilkinson, D. G. (1996) · Methods in cell biology · doi:10.1016/s0091-679x(08)60630-5 · Cited by 379
Self-citationMartin, J. F., Bradley, A., & Olson, E. N. (1995) · Genes & Development · doi:10.1101/gad.9.10.1237 · Cited by 351
Sefton, M., Sánchez, S., & Nieto, M. A. (1998) · Development · doi:10.1242/dev.125.16.3111 · Cited by 315
Self-citationHeart Fields and Cardiac Morphogenesis
Kelly, R. G., Buckingham, M. E., & Moorman, A. F. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a015750 · Cited by 283
Type ID unconventional myosin controls left–right asymmetry in Drosophila
Spéder, P., Adám, G., & Noselli, S. (2006) · Nature · doi:10.1038/nature04623 · Cited by 230
Lin, A. E., Krikov, S. V., Riehle‐Colarusso, T. J., Frías, J. L., Belmont, J. W., Anderka, M., Geva, T., Getz, K., Botto, L. D., & Study, T. N. B. D. P. (2014) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.36695 · Cited by 222
Left–right asymmetry in the vertebrate embryo: from early information to higher-level integration
Raya, Á., & Belmonte, J. C. I. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1830 · Cited by 220
T-box gene tbx5 is essential for formation of the pectoral limb bud
Ahn, D., Kourakis, M. J., Rohde, L. A., Silver, L. M., & Ho, R. K. (2002) · Nature · doi:10.1038/nature00814 · Cited by 219
Ramsdell, A. F. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.07.038 · Cited by 200
The Transfer of Left-Right Positional Information during Chick Embryogenesis
Pagán-Westphal, S. M., & Tabin, C. J. (1998) · Cell · doi:10.1016/s0092-8674(00)81143-5 · Cited by 199
Cell Movements at Hensen’s Node Establish Left/Right Asymmetric Gene Expression in the Chick
Gros, J., Feistel, K., Viebahn, C., Blum, M., & Tabin, C. J. (2009) · Science · doi:10.1126/science.1172478 · Cited by 189
Identification and Functional Characterization of Cardiac Pacemaker Cells in Zebrafish
Tessadori, F., van Weerd, J. H., Burkhard, S. B., Verkerk, A. O., de Pater, E., Boukens, B. J., Vink, A., Christoffels, V. M., & Bakkers, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047644 · Cited by 186
Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs
Rowe, R. G., Li, X.-Y., Hu, Y., Saunders, T. L., Virtanen, I., de Herreros, A. G., Becker, K., Ingvarsen, S., Engelholm, L. H., Bommer, G. T., et al. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200810113 · Cited by 161
Tbx5-Hedgehog Molecular Networks Are Essential in the Second Heart Field for Atrial Septation
Xie, L., Hoffmann, A. D., Burnicka-Turek, O., Friedland‐Little, J. M., Zhang, K., & Moskowitz, I. P. G. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.06.006 · Cited by 160
The Hypoblast of the Chick Embryo Positions the Primitive Streak by Antagonizing Nodal Signaling
Bertocchini, F., & Stern, C. D. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00318-0 · Cited by 158
Early Mesodermal Cues Assign Avian Cardiac Pacemaker Fate Potential in a Tertiary Heart Field
Bressan, M. C., Liu, G., & Mikawa, T. (2013) · Science · doi:10.1126/science.1232877 · Cited by 156
Smad5 Is Essential for Left–Right Asymmetry in Mice
Chang, H., Zwijsen, A., Vogel, H. S., Huylebroeck, D., & Matzuk, M. M. (2000) · Developmental Biology · doi:10.1006/dbio.1999.9594 · Cited by 152
Zebrafish cardiac development requires a conserved secondary heart field
Hami, D., Grimes, A. C., Tsai, H., & Kirby, M. L. (2011) · Development · doi:10.1242/dev.061473 · Cited by 147
Rana, M. S., Théveniau‐Ruissy, M., Bono, C. D., Mesbah, K., Francou, A., Rammah, M., Dominguez, J. N., Roux, M., Laforest, B., Anderson, R. H., et al. (2014) · Circulation Research · doi:10.1161/circresaha.115.305020 · Cited by 143
Murray, S. A., & Gridley, T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602234103 · Cited by 128
A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality
Noël, E. S., Verhoeven, M. C., Lagendijk, A. K., Tessadori, F., Smith, K., Choorapoikayil, S., den Hertog, J., & Bakkers, J. (2013) · Nature Communications · doi:10.1038/ncomms3754 · Cited by 127
Chapter 9 In Situ Hybridization Analysis of Chick Embryos in Whole‐Mount and Tissue Sections
Acloque, H., Wilkinson, D. G., & Nieto, M. A. (2008) · Methods in cell biology · doi:10.1016/s0091-679x(08)00209-4 · Cited by 121
Self-citationItasaki, N., Nakamura, H., Sumida, H., & Yasuda, M. (1991) · Anatomy and Embryology · doi:10.1007/bf00185832 · Cited by 116
Modularity and reshuffling of Snail and Slug expression during vertebrate evolution
Locascio, A., Manzanares, M., Blanco, M. J., & Nieto, M. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.262525399 · Cited by 109
Self-citationDominguez, J. N., Meilhac, S. M., Bland, Y. S., BUCKINGHAM, M. E., & Brown, N. A. (2012) · Circulation Research · doi:10.1161/circresaha.112.271247 · Cited by 109
Bergwerff, M., Groot, A. C. G., Wisse, L. J., DeRuiter, M. C., Wessels, A., Martin, J. F., Olson, E. N., & Kern, M. J. (2000) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/pl00008193 · Cited by 94
Evolutionary history of the Snail/Scratch superfamily
Barrallo‐Gimeno, A., & Nieto, M. A. (2009) · Trends in Genetics · doi:10.1016/j.tig.2009.04.001 · Cited by 77
Self-citationActomyosin-driven left-right asymmetry: from molecular torques to chiral self organization
Naganathan, S. R., Middelkoop, T. C., Fürthauer, S., & Grill, S. W. (2016) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2016.01.004 · Cited by 69
Patel, K., Isaac, A., & Cooke, J. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80267-x · Cited by 64
Shaping the zebrafish heart: From left–right axis specification to epithelial tissue morphogenesis
Bakkers, J., Verhoeven, M. C., & Abdelilah‐Seyfried, S. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.04.011 · Cited by 62
Unilateral Dampening of Bmp Activity by Nodal Generates Cardiac Left-Right Asymmetry
Veerkamp, J., Rudolph, F., Cseresnyés, Z., Priller, F. C., Otten, C., Renz, M., Schaefer, L., & Abdelilah‐Seyfried, S. (2013) · Developmental Cell · doi:10.1016/j.devcel.2013.01.026 · Cited by 61
Schlueter, J., & Brand, T. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811944106 · Cited by 55
Palladin regulation of the actin structures needed for cancer invasion
Najm, P., & El‐Sibai, M. (2013) · Cell Adhesion & Migration · doi:10.4161/cam.28024 · Cited by 46
Bayraktar, M., & Männer, J. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00112 · Cited by 46
The role of mechanical forces in the torsional component of cardiac looping
Taber, L. A., Voronov, D. A., & Ramasubramanian, A. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05089.x · Cited by 45
The zebrafish as a novel system for functional genomics and therapeutic development applications.
Nasevicius, A., & Ekker, S. C. (2001) · PubMed · Cited by 39
Snail genes at the crossroads of symmetric and asymmetric processes in the developing mesoderm
Morales, A. V., Acloque, H., Ocaña, O. H., de Frutos, C. A., Gold, V., & Nieto, M. A. (2006) · EMBO Reports · doi:10.1038/sj.embor.7400867 · Cited by 30
Self-citationSnail2 and Zeb2 repress P-cadherin to define embryonic territories in the chick embryo
Acloque, H., Ocaña, O. H., Abad, D., Stern, C. D., & Nieto, M. A. (2017) · Development · doi:10.1242/dev.142562 · Cited by 28
Self-citationActin polymerization is stimulated by actin cross-linking protein palladin
Gurung, R., Yadav, R., Brungardt, J. G., Orlova, A., Egelman, E. H., & Beck, M. R. (2015) · Biochemical Journal · doi:10.1042/bj20151050 · Cited by 27
Left-Right Asymmetry in Vertebrate Development
López-Gracia, M. L., & Ros, M. A. (2007) · Springer eBooks · doi:10.1007/978-3-540-36348-4 · Cited by 17
Cell Tracking Using Photoconvertible Proteins During Zebrafish Development
Lombardo, V. A., Sporbert, A., & Abdelilah‐Seyfried, S. (2012) · Journal of Visualized Experiments · doi:10.3791/4350 · Cited by 17
(2007) · Springer eBooks · doi:10.1007/978-3-540-36348-4_1 · Cited by 5
Flagged first, then by citations
Cited by
Sorted by citations
Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis
Lu, W., & Kang, Y. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.04.010 · Cited by 1,039
Non-redundant functions of EMT transcription factors
Stemmler, M. P., Eccles, R. L., Brabletz, S., & Brabletz, T. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0196-y · Cited by 524
Epithelial plasticity, epithelial-mesenchymal transition, and the TGF-β family
Katsuno, Y., & Derynck, R. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.02.028 · Cited by 187
Huang, Z., Zhang, Z., Zhou, C., Liu, L., & Huang, C. (2022) · MedComm · doi:10.1002/mco2.144 · Cited by 179
Broad applicability of a streamlined Ethyl Cinnamate-based clearing procedure
Masselink, W., Reumann, D., Murawala, P., Pasierbek, P., Taniguchi, Y., Bonnay, F., Meixner, K., Knoblich, J. A., & Tanaka, E. M. (2019) · Development · doi:10.1242/dev.166884 · Cited by 147
Self-citation
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
