1. Cell Biology
  2. Developmental Biology
Download icon

YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

  1. Filipa Neto
  2. Alexandra Klaus-Bergmann
  3. Yu Ting Ong
  4. Silvanus Alt
  5. Anne-Clémence Vion
  6. Anna Szymborska
  7. Joana R Carvalho
  8. Irene Hollfinger
  9. Eireen Bartels-Klein
  10. Claudio A Franco
  11. Michael Potente  Is a corresponding author
  12. Holger Gerhardt  Is a corresponding author
  1. Max Delbrück Centre for Molecular Medicine, Germany
  2. Max Planck Institute for Heart and Lung Research, Germany
  3. Max Delbrück Center for Molecular Medicine, Germany
  4. Instituto de Medicina Molecular, Portugal
Research Article
  • Cited 74
  • Views 7,485
  • Annotations
Cite this article as: eLife 2018;7:e31037 doi: 10.7554/eLife.31037

Abstract

Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting cell migration whilst maintaining barrier function. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels.

Article and author information

Author details

  1. Filipa Neto

    Integrative Vascular Biology, Max Delbrück Centre for Molecular Medicine, Berlin, Germany
    Competing interests
    No competing interests declared.
  2. Alexandra Klaus-Bergmann

    Integrative Vascular Biology, Max Delbrück Centre for Molecular Medicine, Berlin, Germany
    Competing interests
    No competing interests declared.
  3. Yu Ting Ong

    Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3407-2515
  4. Silvanus Alt

    Integrative Vascular Biology, Max Delbrück Centre for Molecular Medicine, Berlin, Germany
    Competing interests
    No competing interests declared.
  5. Anne-Clémence Vion

    Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2788-2512
  6. Anna Szymborska

    Integrative Vascular Biology, Max Delbrück Centre for Molecular Medicine, Berlin, Germany
    Competing interests
    No competing interests declared.
  7. Joana R Carvalho

    Vascular Morphogenesis Laboratory, Instituto de Medicina Molecular, Lisbon, Portugal
    Competing interests
    No competing interests declared.
  8. Irene Hollfinger

    Integrative Vascular Biology, Max Delbrück Centre for Molecular Medicine, Berlin, Germany
    Competing interests
    No competing interests declared.
  9. Eireen Bartels-Klein

    Integrative Vascular Biology, Max Delbrück Centre for Molecular Medicine, Berlin, Germany
    Competing interests
    No competing interests declared.
  10. Claudio A Franco

    Vascular Morphogenesis Laboratory, Instituto de Medicina Molecular, Lisbon, Portugal
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2861-3883
  11. Michael Potente

    Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    michael.potente@mpi-bn.mpg.de
    Competing interests
    No competing interests declared.
  12. Holger Gerhardt

    Integrative Vascular Biology, Max Delbrück Centre for Molecular Medicine, Berlin, Germany
    For correspondence
    holger.gerhardt@mdc-berlin.de
    Competing interests
    Holger Gerhardt, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3030-0384

Funding

H2020 European Research Council (Consolidator Grant Reshape 311719)

  • Holger Gerhardt

H2020 European Research Council (Starting Grant ANGIOMET (311546))

  • Michael Potente

Deutsche Forschungsgemeinschaft (SFB 834)

  • Michael Potente

Excellence Cluster Cardiopulmonary System (EXC 147/1)

  • Michael Potente

LOEWE Research Initiatives Network (Ub-Net)

  • Michael Potente

Stiftung Charité

  • Michael Potente

European Molecular Biology Organization (Young Investigator Programme)

  • Michael Potente

Portugal2020 Program (LISBOA-01-0145-FEDER-00739)

  • Claudio A Franco

Fundação para a Ciência e a Tecnologia (SFRH/BD/51287/2010)

  • Filipa Neto

European Molecular Biology Organization (Long-Term Fellowship ALTF 1625-2014)

  • Anna Szymborska

Deutsches Zentrum für Herz-Kreislaufforschung (REMODEL)

  • Alexandra Klaus-Bergmann
  • Anne-Clémence Vion
  • Eireen Bartels-Klein
  • Holger Gerhardt

H2020-TWINN-2015 (ReTuBi-692322)

  • Claudio A Franco

Fundação para a Ciência e a Tecnologia (SFRH/BD/52224/2013​​)

  • Joana R Carvalho

Fundação para a Ciência e a Tecnologia (FCT Investigator IF/00412/2012)

  • Claudio A Franco

H2020 European Research Council (EC-ERC Starting Grant AXIAL.EC-679368)

  • Claudio A Franco

Fundação para a Ciência e a Tecnologia (EXPL/BEX-BCM/2258/2013)

  • Claudio A Franco

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures involving handling of living animals were performed in accordance with: the United Kingdom's Home Office Animal Act 1986 under the authority of project licence PPL 80/2391 (experiments done in LRI-CRUK); the German animal protection law with approval by the regional offices for health and social services LaGeSo, under the animal licence IC113 G 0117/15 (experiments done in MDC); institutional guidelines and laws, following protocols approved by local animal ethics committees and authorities (B2/1061; Regierungspraesidium Darmstadt) (experiments done at the MPI for Heart and Lung Research).

Reviewing Editor

  1. Reinhard Fässler, Max Planck Institute of Biochemistry, Germany

Publication history

  1. Received: August 4, 2017
  2. Accepted: February 2, 2018
  3. Accepted Manuscript published: February 5, 2018 (version 1)
  4. Version of Record published: February 15, 2018 (version 2)

Copyright

© 2018, Neto et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 7,485
    Page views
  • 1,319
    Downloads
  • 74
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Haibin Yang et al.
    Research Article Updated

    Communications between actin filaments and integrin-mediated focal adhesion (FA) are crucial for cell adhesion and migration. As a core platform to organize FA proteins, the tripartite ILK/PINCH/Parvin (IPP) complex interacts with actin filaments to regulate the cytoskeleton-FA crosstalk. Rsu1, a Ras suppressor, is enriched in FA through PINCH1 and plays important roles in regulating F-actin structures. Here, we solved crystal structures of the Rsu1/PINCH1 complex, in which the leucine-rich-repeats of Rsu1 form a solenoid structure to tightly associate with the C-terminal region of PINCH1. Further structural analysis uncovered that the interaction between Rsu1 and PINCH1 blocks the IPP-mediated F-actin bundling by disrupting the binding of PINCH1 to actin. Consistently, overexpressing Rsu1 in HeLa cells impairs stress fiber formation and cell spreading. Together, our findings demonstrated that Rsu1 is critical for tuning the communication between F-actin and FA by interacting with the IPP complex and negatively modulating the F-actin bundling.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Qiuying Liu et al.
    Research Article Updated

    The regulation of stem cell fate is poorly understood. Genetic studies in Caenorhabditis elegans lead to the hypothesis that a conserved cytoplasmic double-negative feedback loop consisting of the RNA-binding protein Trim71 and the let-7 microRNA controls the pluripotency and differentiation of stem cells. Although let-7-microRNA-mediated inhibition of Trim71 promotes differentiation, whether and how Trim71 regulates pluripotency and inhibits the let-7 microRNA are still unknown. Here, we show that Trim71 represses Ago2 mRNA translation in mouse embryonic stem cells. Blocking this repression leads to a specific post-transcriptional increase of mature let-7 microRNAs, resulting in let-7-dependent stemness defects and accelerated differentiation in the stem cells. These results not only support the Trim71-let-7-microRNA bi-stable switch model in controlling stem cell fate, but also reveal that repressing the conserved pro-differentiation let-7 microRNAs at the mature microRNA level by Ago2 availability is critical to maintaining pluripotency.