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HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development

Author

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  • Sébastien Gauvrit

    (Max Planck Institute for Heart and Lung Research)

  • Alethia Villasenor

    (Max Planck Institute for Heart and Lung Research)

  • Boris Strilic

    (Max Planck Institute for Heart and Lung Research)

  • Philip Kitchen

    (University of Birmingham)

  • Michelle M. Collins

    (Max Planck Institute for Heart and Lung Research)

  • Rubén Marín-Juez

    (Max Planck Institute for Heart and Lung Research)

  • Stefan Guenther

    (Max Planck Institute for Heart and Lung Research)

  • Hans-Martin Maischein

    (Max Planck Institute for Heart and Lung Research)

  • Nana Fukuda

    (Max Planck Institute for Heart and Lung Research)

  • Maurice A. Canham

    (MRC Centre for Regenerative Medicine)

  • Joshua M. Brickman

    (University of Copenhagen)

  • Clifford W. Bogue

    (Yale University School of Medicine)

  • Padma-Sheela Jayaraman

    (University of Birmingham)

  • Didier Y. R. Stainier

    (Max Planck Institute for Heart and Lung Research)

Abstract

Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis.

Suggested Citation

  • Sébastien Gauvrit & Alethia Villasenor & Boris Strilic & Philip Kitchen & Michelle M. Collins & Rubén Marín-Juez & Stefan Guenther & Hans-Martin Maischein & Nana Fukuda & Maurice A. Canham & Joshua M., 2018. "HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05039-1
    DOI: 10.1038/s41467-018-05039-1
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    Cited by:

    1. Thomas Juan & Agatha Ribeiro da Silva & Bárbara Cardoso & SoEun Lim & Violette Charteau & Didier Y. R. Stainier, 2023. "Multiple pkd and piezo gene family members are required for atrioventricular valve formation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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