VANGL2 shapes the mouse heart tube from adjacent epithelia and without planar polarity
Posted on: 19 November 2025 , updated on: 20 November 2025
Preprint posted on 5 September 2025
Planar cell polarity protein, Vangl2, goes out of its way to shape the heart through a planar polarity-independent mechanism.
Selected by Anubhav Prakash
Categories: cell biology, developmental biology, genetics
Why I highlight this work?
Shapes and patterns have fascinated biologists for centuries (1), and when that shape gets tied to the functionality of an organ, it’s no longer just a fascination. It becomes a vital part of biomedical relevance, as seen in the case of heart shaping.
In this preprint, Paul Palmquist-Gomes and colleagues have studied the shaping of the heart tube during development, and their observations spark two important points of debate. First, the role of the gene Vangl2 in epithelial morphogenesis as a regulator of exchange in cell neighbours. Second, the autonomy of an organ during development.
The observations made by the authors are fascinating and should be of particular interest to researchers working on morphogenesis, planar cell polarity and epithelial reorganisation.
Background
During development, the shaping of the heart tube is driven by a coordinated set of morphological events (2) simultaneously with the organogenesis of nearby organs like the neural tube. The morphological process of forming a tube from an epithelial sheet and shaping it is governed by asymmetric forces (3). One example is the asymmetric recruitment of the planar cell polarity protein, VANGL2, on the junctions (3, 4). This protein, in turn, recruits actin regulators and drives the process of forming and shaping a heart tube (5). A point mutant of Vangl2, called looptail, shows defects in the shaping of the heart but also in other tissues, raising the question of whether it is a secondary effect from nearby tissues (6). Also, Vangl2 seems to be indispensable for the morphogenesis of the heart (7).
Building on these studies, Palmquist-Gomes and colleagues have analysed the mechanism explaining how Vangl2 might regulate epithelial remodelling and how different parts of the heart contribute to this process.
Key Findings
Role of Vangl2 in shaping the heart. This study combines genetics and 3D imaging to first quantify the defects in heart shape in Vangl2 mutants. At embryonic day (E) 9.5, when heart looping is complete, the position of ventricles with respect to the left-right axis was perturbed in mutants. Also, the outflow tract (OFT) was shorter. The authors found that these defects became more severe at E10.5 and were also present in mutants where the neural tube had closed properly. This allowed them to infer the role of Vangl2 in heart looping independent of neural tube development.
Parts of heart contribute to different morphogenetic processes
The authors deleted Vangl2 specifically in the mesoderm that contains cardiac progenitors. The mutants showed a shorter OFT, but not the perturbed positioning of ventricles, suggesting an independent mechanism driving these two phenotypes. Interestingly, the deletion of Vangl2 from posterior cardiac precursors led to mutants with normal OFT but an abnormal ventricle position.
Analysing the activity pattern of Hoxb1Cre and Mesp1Cre, the authors argue that the caudal splanchnic mesoderm, which is specifically marked by Hoxb1Cre, anchors the heart tube and helps in maintaining it in the midline. This suggests that although the heart is a single organ, one aspect of morphogenesis could be influenced differently by different subsets of cells.
VANGL2 remodels epithelia by resolving cell-intercalation
The author team then dissected out the mechanism by first investigating the localisation of VANGL2 on cell junctions. Interestingly, they found that VANGL2 is low and symmetrical on cell-cell junctions but shows a higher accumulation on vertices where 4 or more cells meet. These rosette-like structures increased in Mesp1Cre-driven Vangl2 mutants. This suggests that the elongation of the OFT is driven by epithelial remodelling, where VANGL2 regulates the resolution of the multicellular rosettes. In the Hoxb1Cre-positive splanchnic mesoderm, VANGL2 and an actin regulator, SHROOM3, show similar occupancy on apical domains. Mutants for Shroom3 phenocopied the Hoxb1Cre-driven mutants of Vangl2, showing disorganisation of epithelia and an altered position of the ventricles without affecting OFT.
References
- “On Growth and Form”. 1914 by D’Arcy Thompson
- Andrés-Delgado, Laura, and Nadia Mercader. “Interplay between cardiac function and heart development.” Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1863, no. 7 (2016): 1707-1716.
- Nishimura, Tamako, Hisao Honda, and Masatoshi Takeichi. “Planar cell polarity links axes of spatial dynamics in neural-tube closure.” Cell 149, no. 5 (2012): 1084-1097.
- Prakash, Anubhav, Julian Weninger, Nishant Singh, Sukanya Raman, Madan Rao, Karsten Kruse, and Raj K. Ladher. “Junctional force patterning drives both positional order and planar polarity in the auditory epithelia.” Nature Communications 16, no. 1 (2025): 3927.
- Lindqvist, Maria, Zachi Horn, Vitezslav Bryja, Gunnar Schulte, Panagiotis Papachristou, Rieko Ajima, Cecilia Dyberg et al. “Vang-like protein 2 and Rac1 interact to regulate adherens junctions.” Journal of cell science 123, no. 3 (2010): 472-483.
- Henderson, Deborah J., Simon J. Conway, Nicholas DE Greene, Dianne Gerrelli, Jennifer N. Murdoch, Robert H. Anderson, and Andrew J. Copp. “Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant.” Circulation research 89, no. 1 (2001): 6-12
- Ramsbottom, Simon A., Vipul Sharma, Hong Jun Rhee, Lorraine Eley, Helen M. Phillips, Hannah F. Rigby, Charlotte Dean, Bill Chaudhry, and Deborah J. Henderson. “Vangl2-regulated polarisation of second heart field-derived cells is required for outflow tract lengthening during cardiac development.” PLoS genetics 10, no. 12 (2014): e1004871.
doi: https://doi.org/10.1242/prelights.42154
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| List by | Vibha SINGH et al. |
March in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) cancer biology 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics and genomics 6) other
| List by | Girish Kale et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
Early 2025 preprints – the genetics & genomics edition
In this community-driven preList, a group of preLighters, with expertise in different areas of genetics and genomics have worked together to create this preprint reading list. Categories include: 1) bioinformatics 2) epigenetics 3) gene regulation 4) genomics 5) transcriptomics
| List by | Chee Kiang Ewe et al. |
January in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Barbora Knotkova et al. |
End-of-year preprints – the genetics & genomics edition
In this community-driven preList, a group of preLighters, with expertise in different areas of genetics and genomics have worked together to create this preprint reading list. Categories include: 1) genomics 2) bioinformatics 3) gene regulation 4) epigenetics
| List by | Chee Kiang Ewe et al. |
BSDB/GenSoc Spring Meeting 2024
A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.
| List by | Joyce Yu, Katherine Brown |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University
This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.
| List by | Nándor Lipták |
20th “Genetics Workshops in Hungary”, Szeged (25th, September)
In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf
| List by | Nándor Lipták |
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
| List by | Nándor Lipták |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
| List by | Jesus Victorino |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |