1. Developmental Biology
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The Hippo pathway effector YAP is an essential regulator of ductal progenitor patterning in the mouse submandibular gland

  1. Aleksander D Szymaniak
  2. Rongjuan Mi
  3. Shannon E McCarthy
  4. Adam C Gower
  5. Taylor L Reynolds
  6. Michael Mingueneau
  7. Maria Kukuruzinska
  8. Xaralabos Varelas  Is a corresponding author
  1. Boston University School of Medicine, United States
  2. Biogen, United States
  3. Boston University School of Dental Medicine, United States
Research Article
  • Cited 21
  • Views 1,740
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Cite this article as: eLife 2017;6:e23499 doi: 10.7554/eLife.23499

Abstract

Salivary glands, such as submandibular glands (SMGs), are composed of branched epithelial ductal networks that terminate in acini that together produce, transport and secrete saliva. Here, we show that the transcriptional regulator Yap, a key effector of the Hippo pathway, is required for the proper patterning and morphogenesis of SMG epithelium. Epithelial deletion of Yap in developing SMGs results in the loss of ductal structures, arising from reduced expression of the EGF family member Epiregulin, which we show is required for the expansion of Krt5/Krt14-positive ductal progenitors. We further show that epithelial deletion of the Lats1 and Lats2 genes, which encode kinases that restrict nuclear Yap localization, results in morphogenesis defects accompanied by an expansion of Krt5/Krt14-positive cells. Collectively, our data indicate that Yap-induced Epiregulin signaling promotes the identity of SMG ductal progenitors and that removal of nuclear Yap by Lats1/2-mediated signaling is critical for proper ductal maturation.

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Article and author information

Author details

  1. Aleksander D Szymaniak

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    No competing interests declared.
  2. Rongjuan Mi

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    No competing interests declared.
  3. Shannon E McCarthy

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    No competing interests declared.
  4. Adam C Gower

    Boston University Clinical and Translational Science Institute, Boston University School of Medicine, Boston, United States
    Competing interests
    No competing interests declared.
  5. Taylor L Reynolds

    Immunology Research, Biogen, Cambridge, United States
    Competing interests
    Taylor L Reynolds, Employee of Biogen.
  6. Michael Mingueneau

    Immunology Research, Biogen, Cambridge, United States
    Competing interests
    Michael Mingueneau, Employee of Biogen.
  7. Maria Kukuruzinska

    Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, United States
    Competing interests
    No competing interests declared.
  8. Xaralabos Varelas

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    For correspondence
    xvarelas@bu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2882-4541

Funding

March of Dimes Foundation (1-FY14-219)

  • Xaralabos Varelas

National Heart, Lung, and Blood Institute (R01 HL124392)

  • Xaralabos Varelas

Sjogren's Syndrome Foundation (Research Grant)

  • Xaralabos Varelas

National Institute of Dental and Craniofacial Research (R21 DE024954)

  • Maria Kukuruzinska

National Center for Advancing Translational Sciences (UL1-TR001430)

  • Adam C Gower
  • Xaralabos Varelas

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.Animal care and handling was consistent with the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association. Prior to the initiation of experiments, all study protocols were reviewed and modified according to the suggestions of the Boston University School of Medicine IACUC. The Boston University School of Medicine animal management program is accredited by the American Association for the Accreditation of Laboratory Animal Care, and meets National Institutes of Health standards as set forth in the Guide for the Care and Use of Laboratory Animals (DHHS Pub.No. (NIH) 85-23, rev 1985). Boston University's Animal Welfare Assurance number is A-3316-01.

Reviewing Editor

  1. Clare Blackburn, MRC Centre for Regenerative Medicine, University of Edinburgh, United Kingdom

Publication history

  1. Received: November 22, 2016
  2. Accepted: May 8, 2017
  3. Accepted Manuscript published: May 11, 2017 (version 1)
  4. Version of Record published: June 9, 2017 (version 2)

Copyright

© 2017, Szymaniak 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.

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